Filed on Behalf of Ethicon, Inc. Paper No

Filed on behalf of Ethicon, Inc. Paper No. ___ By: Dianne B. Elderkin ([email protected]) Date Filed: March 26, 2015 Steven D. Maslowski ([email protected]) AKIN GUMP STRAUSS HAUER & FELD LLP Two Commerce Square 2001 Market Street, Suite 4100 Philadelphia, PA 19103 Tel: (215) 965-1200 Fax: (215) 965-1210

UNITED STATES PATENT AND TRADEMARK OFFICE

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BEFORE THE PATENT TRIAL AND APPEAL BOARD

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ETHICON, INC. Petitioner

BAXTER INTERNATIONAL INC. AND BAXTER HEALTHCARE S.A. Patent Owners

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Case IPR: Unassigned ______

PETITION FOR INTER PARTES REVIEW OF UNITED STATES PATENT NO. 6,066,325

TABLE OF CONTENTS

I. MANDATORY NOTICES UNDER 37 C.F.R § 42.8(a)(1) ...... 1 A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) ...... 1 B. Related Matters Under 37 C.F.R. § 42.8(b)(2) ...... 1 C. Lead and Back-Up Counsel and Service Information ...... 1 II. PAYMENT OF FEES – 37 C.F.R. § 42.103 ...... 2 III. REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104 ...... 2 A. Grounds for Standing Under § 42.104(a) ...... 2 B. Challenge Under § 42.104(b) and Relief Requested ...... 2 IV. SUMMARY OF THE ’325 PATENT ...... 4 A. Brief Description ...... 4 B. Summary of the Prosecution History of the ’325 Patent ...... 5 C. State of the Art at the Time of the Alleged Invention Claimed in the ’325 Patent ...... 5 V. CLAIM CONSTRUCTION UNDER 37 C.F.R. §§ 42.104(b)(3) ...... 7 A. “Fragmented” (claims 1-8) ...... 7 B. “Hydrogel,” “gel” (claims 1-8) ...... 8 C. “Partially hydrated” and “fully hydrated” (claims 1-8) ...... 9 D. “Substantially free from an aqueous phase” (claims 1-8) ...... 10 E. “Subunit size in the range from 0.01 mm to 5 mm when fully hydrated” (claims 1-8) ...... 11 F. “Equilibrium swell” (claims 1-8) ...... 12 G. “Active agent” (claims 3-8) ...... 13 VI. EVERY CLAIM OF THE ’325 PATENT FOR WHICH IPR IS REQUESTED IS UNPATENTABLE ...... 14 A. Ground 1: Ikada Anticipates Claims 1-3, and 6 ...... 15 1. Ikada Anticipates Claim 1 ...... 19 2. Ikada Anticipates Claim 2 ...... 26 3. Ikada Anticipates Claim 3 ...... 26 4. Ikada Anticipates Claim 6 ...... 27 B. Ground 2: Sakamoto in View of Schramm Renders Obvious Claims 1-8 27 1. Motivation to Combine Sakamoto and Schramm ...... 31 2. Sakamoto in View of Schramm Renders Claim 1 Obvious ...... 34 3. Sakamoto in View of Schramm Renders Claim 2 Obvious ...... 41

4. Sakamoto in View of Schramm Renders Claims 3, 4, and 5 Obvious ...... 42 5. Sakamoto in View of Schramm Renders Claim 6 Obvious ...... 43 6. Sakamoto in View of Schramm Renders Claim 7 Obvious ...... 43 7. Sakamoto in View of Schramm Renders Claim 8 Obvious ...... 44 C. Ground 3: Ikada in view of Sakamoto Renders Obvious Claims 1-8 .... 45 1. Motivation to Combine Ikada and Sakamoto ...... 45 1. Ikada in View of Sakamoto Renders Claim 1 Obvious ...... 47 2. Ikada in View of Sakamoto Renders Claim 2 Obvious ...... 53 3. Ikada in View of Sakamoto Renders Claim 3 Obvious ...... 53 4. Ikada in View of Sakamoto Renders Claims 4 and 5 Obvious ..... 54 5. Ikada in View of Sakamoto Renders Claim 6 Obvious ...... 55 6. Ikada in View of Sakamoto Renders Claim 7 Obvious ...... 56 7. Ikada in View of Sakamoto Renders Claim 8 Obvious ...... 56 VII. SECONDARY CONSIDERATIONS ...... 57 VIII. CONCLUSION ...... 60

LIST OF EXHIBITS

Ethicon Exhibit Description No. Ex. 1001 U.S. Patent Number 6,066,325 to Wallace et al. (the “’325 Patent”) Ex. 1002 Excerpts from the Prosecution History of the ’325 Patent (the “Prosecution History”) Ex. 1003 Declaration of Dr. David J. Mooney Ex. 1004 Curriculum Vitae of Dr. David J. Mooney Ex. 1005 U.S. Patent Number 6,831,058 to Ikada et al. (“Ikada”) Ex. 1006 EP Publication No. EP 0 172 710 to Sakamoto et al. (“Sakamoto”) Ex. 1007 Schramm, V.L., Lavorato, A. S., Gelfoam Paste Injec- tion for Vocal Cord Paralysis: Temporary Rehabilitation of Glottic Incompetence, The Laryngoscope 88:1978 (“Schramm”) Ex. 1008 Cantor and Reynolds, Gelfoam and Thrombin in Gas- troduodenal Bleeding, J. Lab. Clinical Medicine 35:890- 893 (1950) (“Cantor”) Ex. 1009 Krill et al., Topical Thorombin and Powered Gelfoam: An Efficient Hemostatic Treatment for Surgery, Journal of Tennesee Dental Association 66(2):26-27 (1986) (“Krill”) Ex. 1010 Guinto, Preparation of Gelfoam Particles Using and Or- thopedic Rasp, Radiology 153:260 (1984) (“Guinto”)

Ex. 1011 U.S. Patent Number 3,896,815 to Fettel et al. (the “’815 Patent) Ex. 1012 Peppas and Barr-Howell, Chapter 2: Characterization of the Cross-Linked Structure of Hydrogels, from Hydro- gels in Medicine and Pharmacy, Vol. I: Fundamentals, 1987 (“Peppas”) Ex. 1013 Lewis et al., Comparison of Two Gelatin and Thrombin Combination Hemostats in a Porcine Liver Abrasion Model, Journal of Investigative Surgery, Early Online 2013 (“Lewis”)

iii

Ex. 1014 Sakurabayashi. S. et al., Clinical Evaluation of a New Hemostatic Agent for Liver Biopsy, Fourth Dept. of In- ternal Medicine Tokyo Medical College, 30(10):2249- 2256 (1988) (in English (“Sakurabayashi”) Ex. 1015 Sakurabayashi. S. et al., Clinical Evaluation of a New Hemostatic Agent for Liver Biopsy, Fourth Dept. of In- ternal Medicine Tokyo Medical College, 30(10):2249- 2256 (1988) (in Japanese) (“Sakurabayashi”) Ex. 1016 Flory, P., “Phase Equilibria,” Principles of Polymer Chemistry, Cornell University Press, (1953) (“Flory”) Ex. 1017 Gelfoam® Plus - Powder Hemostasis Kit Instructions for Use Ex. 1018 Herndon, J., et al. Compression of the Brain and Spinal Cord Following Use of Gelfoam, Archives of Surgery, Vol. 104:107 (Jan. 1972) (“Herndon”) Ex. 1019 Antalek, B. Magnetic Resonance Imaging Studies of the Behavior of Fluids in Gelatin and Other Porous Ma- terials. Thesis. Submitted to the Graduate School of the Rochester Institute of Technology, Rochester, NY (Feb. 1991) Ex. 1020 Franks, F., ed., Water, a Comprehensive Treatise, Vol- ume 1, Introduction. (Plenum Press, NY 1972) Ex. 1021 Notice of a Lawsuit and Waiver of Summons executed by Ethicon Inc. in the matter of Baxter International Inc., et al. v. Johnson & Johnson, et al., Civil Action No. 1:14cv00498, N.D. Ill. Ex. 1022 Notice of a Lawsuit and Waiver of Summons executed by Johnson & Johnson in the matter of Baxter Interna- tional Inc., et al. v. Johnson & Johnson, et al., Civil Ac- tion No. 1:14cv00498, N.D. Ill. Ex. 1023 Notice of Institution of ITC Investigation, 337-TA-913 Ex. 1024 Complaint of Baxter International Inc., Baxter Healthcare Corporation, and Baxter Healthcare SA Un- der Section 337 of the Tariff Act of 1930, As Amended, 337-TA-913

Ethicon, Inc. (“Petitioner” or “Ethicon”) petitions for Inter Partes Review

(“IPR”) under 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42 of claims 1-8 (“the Chal- lenged Claims”) of U.S. Patent No. 6,066,325 (the “’325 Patent”). As explained below, there exists a reasonable likelihood that Petitioner will prevail in demonstrating unpatentability of at least one Challenged Claim based on teachings set forth in the references presented in this petition.

I. MANDATORY NOTICES UNDER 37 C.F.R § 42.8(a)(1)

A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1)

Ethicon is a real party-in-interest. Ethicon is a wholly-owned subsidiary of

Johnson & Johnson (“J&J”), which is also a real party-in-interest.

B. Related Matters Under 37 C.F.R. § 42.8(b)(2) Petitioner is not aware of any disclaimers, reexamination certificates or petitions for IPR for the ’325 Patent. The ’325 Patent is the subject of Civil Action

Number 1:14-cv-00498 (N.D. Ill.) filed on January 23, 2014 (the “District Court

Action”) (currently stayed), and U.S. International Trade Commission Investiga- tion No. 337-TA-913 filed on February 28, 2014 (the “ITC Action”).

C. Lead and Back-Up Counsel and Service Information

Petitioner designates Dianne B. Elderkin, Reg. No. 28,598, as Lead Counsel and Steven D. Maslowski, Reg. No. 46,905, as Backup Counsel, both available at

Two Commerce Square, 2001 Market Street, Suite 4100, Philadelphia, PA 19103

(T: 215.965.1200; F: 215.965.1210), or electronically by email at ETHI-

[email protected].

II. PAYMENT OF FEES – 37 C.F.R. § 42.103 Petitioner authorizes the Patent and Trademark Office (“Office”) to charge

Deposit Account No. 50-2310 for the fee set in 37 C.F.R. § 42.15(a) for this Peti- tion and further authorizes for any additional fees to be charged to this account.

III. REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104

A. Grounds for Standing Under § 42.104(a) Petitioner certifies that the ’325 Patent is available for IPR. The present petition is being filed within one year of the filing of the “Notice of a Lawsuit and Re- quest to Waive Service of a Summons,” which Ethicon and J&J filed on March 26,

2014 in the District Court Action. See Ex. 1021; Ex. 1022. Furthermore, the present petition is being filed within one year of service of the ITC complaint, which was effected on April 2, 2014 in the ITC Action. See Ex. 1023. Petitioner is not barred or estopped from requesting this review on the below-identified grounds.

B. Challenge Under § 42.104(b) and Relief Requested Petitioner requests IPR of the Challenged Claims on the grounds set forth in

the table shown below, and requests that each of the Challenged Claims be found

unpatentable. An explanation of unpatentability under the grounds identified below

is provided in the form of the detailed description that follows, indicating where

each element can be found in the cited prior art, and the relevance of that prior art.

In particular, the claims of the ’325 Patent relate to fragmented, cross-linked

gelatin hydrogels that swell (i.e., absorb water or buffer) to within a specified range. But, as explained below, there is nothing new about such materials and there is nothing critical or even advantageous about the swell range recited in the claims.

The prior art discloses exactly the types of hydrogels claimed, and any variations in the art from what is claimed are trivial, and well within the ordinary skill in the art. Additional explanation and support for each ground of rejection is set forth in

Ex. 1003, Declaration of Dr. David J. Mooney.

Ground ’325 Patent Claims Basis for Rejection

Ground 1 1-3, 6 §102: Ikada

Ground 2 1-8 §103: Sakamoto in view of Schramm

Ground 3 1-8 §103: Ikada in view of Sakamoto

Ikada (Ex. 1005) qualifies as prior art at least under 35 U.S.C. § 102(e) be-

cause its filing date predates the invention date of the ’325 Patent. Specifically,

Ikada was filed (as application No. 08/567,355) on November 30, 1995, which was

before August 27, 1996—the earliest filing date of any application to which the

’325 Patent claims priority. See Section IV.B. Sakamoto (Ex. 1006) qualifies as

prior art at least under 35 U.S.C. § 102(b) because Sakamoto published on March

11, 1992, more than one year prior to the claimed August 27, 1996 priority date.

Schramm (Ex. 1007) qualifies as prior art at least under 35 U.S.C. § 102(b) because it published in 1978, more than one year prior to the claimed priority date.

IV. SUMMARY OF THE ’325 PATENT

A. Brief Description The ’325 Patent disclosure “relates generally to biocompatible cross-linked polymeric compositions and to the use of such compositions for the controlled delivery of aqueous agents to target sites.” Ex. 1001, 1:17-20. Although the specification discloses a broad group of polymeric compositions (id., 11:18-39), the pa-

tent claims are directed to gelatin hydrogels. The specification discloses a broad

group of “active agents” that can be delivered to targets sites (id. 12:62-13:22), and

also discloses a “specific use in stopping or inhibiting bleeding (hemostasis), par-

ticularly when combined with a suitable hemostatic agent, such as thrombin, fi-

brinogen, clotting factors, and the like” (id., 4:18-21). The’325 Patent claims,

which refer to an active agent, recite clotting agents or, specifically, thrombin.

As discussed below, the term “hydrogel” is expressly defined in the patent,

but, generally, a hydrogel material is one that is capable of absorbing an aqueous

medium. The patent claims characterize the recited gelatin hydrogels, inter alia,

by their “equilibriums well,” which is a measure of how much aqueous medium

the hydrogel can absorb. The claims also require that the hydrogels be “fragment-

ed” with a “subunit size” in the range from 0.01 mm to 5 mm when fully hydrated.

B. Summary of the Prosecution History of the ’325 Patent

The ’325 Patent issued on May 23, 2000 from an application filed on Febru-

ary 27, 1998 (U.S. patent application No. 09/032,370), which claims priority to a

provisional application No. 60/050,437 filed on June 18, 1997 and—through a se-

rious of continuation-in-part applications—also claims priority to an Application

No. 08/704,852, which was filed on August 27, 1996.

On August 3, 1999, the Applicants held an interview with the Examiner fol-

lowing a non-final Office Action in which all of the then-pending claims had either

been rejected under 35 U.S.C. §102 or not considered on the merits due to improp-

er form. Ex. 1002, pp. 51, 54-56, 59. In the Interview Summary, the Examiner

suggested to the Applicants the addition of the following elements to independent

Claim 1: (1) the hydrogel is a gelatin; (2) the gelatin has a subunit size when fully

hydrated in the range of 0.01 mm to 5 mm (i.e., limitation of original claim 2); (3)

the gelatin has an equilibrium swell from 400% to 5000% (i.e., limitation of origi-

nal claim 3); and (4) the hydrogel is present in an applicator. Id., p. 59; see also id. at 48. After the Applicants made these suggested amendments to the claims, the

Examiner issued a Notice of Allowability. See id., pp. 60, 63.

C. State of the Art at the Time of the Alleged Invention Claimed in the ’325 Patent

The inventors of the ‘325 Patent were not the first to disclose using fragmented, crosslinked, gelatin materials as hemostats. To the contrary, a fragmented,

biocompatible, cross-linked gelatin, called “Gelfoam,”was sold commercially as a hemostat as early as 1950.” Ex. 1003, ¶¶ 9-10. Two of the prior art references relied upon in this Petition expressly refer to Gelfoam.

In 1978, Schramm described making a paste of Gelfoam powder and saline, putting it into a syringe, and extruding it as a cohesive paste into human tissue. See

Ex. 1007, p. 1269. Although Schramm describes using Gelfoam powder for the treatment of vocal cord paralysis, it also teaches that “Gelfoam® was developed as a hemostatic material.” Id.

Sakamoto, published in 1992, provides an example of mixing Gelfoam powder with thrombin and Factor XIII adsorbed thereto with distilled water in a syringe for use as a hemostatic agent. See Ex. 1006, 5:45-6:5. Especially important for purposes of this petition is that Sakamoto states that Gelfoam has “water- absorption capability of 500-800 weight percent” and is a “mixture of flake substance in its longest dimension from 20 µm to 200 µm.” Id., 5:45-47.

The third reference relied upon in this Petition, Ikada, does not refer to Gel- foam but does disclose cross-linked gelatin hydrogel preparations having various levels of “water content” that can be used as carriers for active agents. Ex. 1005,

2:1-5; Ex. 1003, ¶¶ 70-87.

Before the ‘325 Patent invention, it was known in the art how to engineer a hydrogel to have a desired equilibrium swell by adjusting the amount of crosslink-

ing in the polymeric network. See, e.g., Ex. 1003, ¶¶ 23, 83; Ex. 1016, p. 581 (“The degree of swelling observed at equilibrium . . . invariably decreases with increasing

degrees of cross-linking”). Moreover, methods for cross-linking polymers were

known in the art. See, e.g., Ex. 1003, ¶¶ 113-114.

V. CLAIM CONSTRUCTION UNDER 37 C.F.R. §§ 42.104(b)(3)

Each term of a claim subject to IPR is given its “broadest reasonable con-

struction in light of the specification of the patent in which it appears.”1 37 C.F.R.

§ 42.100(b). Accordingly, for purposes of this proceeding only, Petitioner submits

constructions for the following terms, and submits that all remaining terms should

be given their plain meaning.

A. “fragmented” (claims 1-8) Independent claim 1 recites a “fragmented biocompatible hydrogel.” Ex.

1001, 24:66-25:6. The ’325 Patent repeatedly uses the term “fragmented,” includ-

ing stating:

1 Because the standards of claim interpretation applied in litigation differ from Of- fice proceedings, any interpretation of claim terms in this IPR is not binding upon

Petitioner in any litigation(s) related to the subject patent. See In re Zletz, 893 F.2d.

319, 321-22 (Fed. Cir. 1989).

The hydrogel is resorbable and fragmented, i.e. comprises small subunits having a size and other physical properties which enhance the flowability of the hydrogel (e.g. the ability to be extruded through a syringe) and the ability of the hydrogel to otherwise be applied onto and conform to sites on or in tissue, including tissue surfaces and defined cavities, e.g. intravertebral spaces, tissue divots, holes, pockets, and the like. Ex. 1001, 4:45-52 (emphasis added). Thus, one of skill in the art would understand the broadest reasonable interpretation (“BRI”) of “fragmented” to be “in the form of discrete subunits.” Ex. 1003, ¶ 51.

B. “hydrogel,” “gel” (claims 1-8) Independent claim 1 recites a “fragmented biocompatible hydrogel.” Ex.

1001, 24:66-25:6. Claim 1 also uses the term “the gel” where the antecedent term is “hydrogel,” and thus these terms have the same meaning. Ex. 1003, ¶ 52.

The ’325 Patent states that “[b]y ‘hydrogel,’ it is meant that the composition comprises a single phase aqueous colloid in which a biologic or non-biologic polymer, as defined in more detail below, absorbs water or an aqueous buffer.” Id.,

10:58-61. This express definition contemplates that the “hydrogel” has absorbed water or aqueous buffer. Although the patent indicates that even “dry” materials will have some residual moisture content (id., 8:37-45), the specification also teaches that the material must have a moisture content that is “sufficiently high . . . so that the material will act as a hydrogel.” Id., 5:62-67 (emphasis added); see

also id., 7:9-10 (“The polymer will be capable of being cross-linked and of being hydrated to form a hydrogel.”) (emphasis added). One of ordinary skill in the art would understand that a “hydrogel” has some amount of absorbed water or buffer such that it is not a dry powder. See Ex. 1003, ¶ 54. This is consistent with the patent specification which distinguishes the claimed “hydrogels” from what the patent calls “dry powders” and “starting materials” for making the hydrogels in reference to the amount of water absorbed by the constituent polymer materials. See Ex.

1001, 5:38-43. Thus, one of skill in the art would understand the BRI of “hydro-

gel” or “gel” to be a “single phase aqueous colloid in which a biologic or non-

biologic polymer absorbs water or an aqueous buffer.” Ex. 1003, ¶ 56.

C. “partially hydrated” and “fully hydrated” (claims 1-8) Independent claim 1 recites a “fragmented biocompatible hydrogel which is

at least partially hydrated” and with a certain subunit size “when fully hydrated.”

Ex. 1001, 24:66-67. The patent expressly defines “hydration” as relating to the

amount of water the hydrogel contains relative to the maximum amount of water it

can absorb: “Hydration is defined as the percentage of water contained by the hy-

drogel compared to that contained by the hydrogel when its [sic] fully saturated,

that is, at its equilibrium swell.” Ex. 1001, 8:30-33.

The specification then explains the different degrees of hydration: “A mate-

rial with 0% hydration will be non-swollen. A material with 100% hydration will

be at its equilibrium water content and fully swollen. Hydrations between 0% and

100% will correspond to swelling between the minimum and maximum amounts.”

Id., 8:33-37. The specification also distinguishes “dry powders” from a partially

hydrated hydrogel, or a fully hydrated hydrogel, “depending on the extent of hy-

dration.” Id., 5:15-25. According to the ’325 Patent, the term “dry” specifies “ma-

terials having a low moisture content, usually below 20%, often below 10%, and

frequently below 5% by weight . . . .” Id., 8:41-45. The specification also quanti-

fies the hydration level for “fully hydrated” hydrogels: “When used in regions sur-

rounding nerves and other sensitive body structures, it is preferable to employ fully

hydrated hydrogels (i.e. with >95% of hydration at equilibrium swell) in order to

avoid damage to the nerves from swelling in an enclosed environment.” Id., 15:66–

16:3 (emphasis added).

Based on the disclosure in the ’325 Patent one of skill in the art would un-

derstand the BRI of “partially hydrated” to be “having a moisture content suffi-

cient to be swollen and not a free flowing powder, but less than or equal to the

moisture content corresponding to 95% of the equilibrium swell of the hydrogel

or gelatin gel.” Ex. 1003, ¶ 60. One of skill in the art would understand the BRI

of “fully hydrated” to be “having a moisture content greater than that corre-

sponding to 95% of the equilibrium swell of the hydrogel.” Id.

D. “substantially free from an aqueous phase” (claims 1-8)

Independent claim 1 recites a hydrogel that is “substantially free from an aqueous phase.” Ex. 1001, 24:67-25:1. The ’325 Patent specification explains that

“[b]y ‘substantially free of an aqueous phase’ it is meant that the compositions will be fully or partially hydrated, but will not be hydrated above their capacity to absorb water.” Id., 5:5-7. The ’325 Patent specification also states that:

[A] test for determining whether a composition has a free aqueous phase is set forth in Example 8. Hydrogels that are substantially free of an aqueous phase should release less than 10% by weight aqueous phase when subjected to a 10 lb. force in the test, preferably releasing less than 5% by weight, and more preferably less than 1% by weight, and more preferably releasing no discernable aqueous phase and dis- playing no collapse. Id., 5:8-14.

Based on the disclosure in the ’325 Patent, one of ordinary skill in the art would understand the BRI of “substantially free from an aqueous phase” to be that the material is “fully or partially hydrated, but not hydrated above its capacity to absorb water.” Ex. 1003, ¶ 62.

E. “subunit size in the range from 0.01 mm to 5 mm when fully hydrated” (claims 1-8) Independent claim 1 also states that the gel “has a subunit size in the range from 0.01 mm to 5 mm when fully hydrated.” Ex. 1001, 25:3-4. This claim term is referring to the size of the fragmented units of gel in their fully hydrated state. The

’325 Patent specification states that “the size of particles in the dry powder starting

material (prior to hydration) will determine the partially or fully hydrated size of the subunit (depending on the factors described below).” Id., 5:22-25. Based on

the disclosure in the ’325 Patent, one of ordinary skill in the art would understand

the BRI of “subunit size in the range from 0.01 mm to 5 mm when fully hydrated”

to be that the “characteristic width or diameter of a discrete piece of hydrogel is

in the range from 0.01 mm to 5 mm when fully hydrated.” Ex. 1003, ¶ 63.

F. “equilibrium swell” (claims 1-8) Independent claim 1 states that the hydrogel has “an equilibrium swell from

400% to 5000%.” Ex. 1001, 25:4-5. The ’325 Patent specification states that

“‘[e]quilibrium swell’ is defined as the percent swell at equilibrium after the poly-

meric material has been immersed in a wetting agent for a time period sufficient

for water content to become constant, typically 18 to 24 hours.” Id., 11:9-12.

The definition of “equilibrium swell” includes the term “percent swell.” The

specification defines “percent swell’ as:

the dry weight is subtracted from the wet weight, divided by the dry weight and multiplied by 100, where wet weight is measured after the wetting agent has been removed as completely as possible from the exterior of the material, e.g. by filtration, and where dry weight is measured after exposure to an elevated temperature for a time sufficient to evaporate the wetting agent, e.g., 2 hours at 120° C.

Id., 11:1-8. The formula shown in Equation 1 above is also provided in the patent for determining “percent swell.” Ex. 1001, 21:19-21. As explained by Dr. Mooney,

“percent swell” and other similar terms such as “equilibrium weight swelling ra-

tio,” “water absorption capability,” “percent solids,” or “water content” are param- eters commonly used to characterize a polymer’s ability to absorb water, as shown in the figure below:

Ex. 1003, ¶ 20, 31, 40, 93.

Based on the disclosure in the ’325 Patent, one of ordinary skill in the art would understand the BRI of “equilibrium swell” to be “the percent swell at equi-

librium after the polymeric material has been immersed in a wetting agent for a

time period sufficient for water content to become constant” where “percent

swell” means that “the dry weight is subtracted from the wet weight, divided by the

dry weight and multiplied by 100.” Id., ¶ 66.

G. “active agent” (claims 3-8)

Dependent claim 3 states that the hydrogel is “at least partially hydrated with an aqueous medium comprising an active agent.” Ex. 1001, 25:9-11. The ’325 Pa- tent states that “active agents can provide biological activity even prior to release from the product matrix.” Id., 3:3-5. The patent also states that “[t]he methods and compositions will be particularly useful for delivering drugs and other active agents, such as biological macromolecules, polypeptides, oligopeptides, nucleic acids, small molecule drugs, and the like.” Id., 4:1-5. Based on the disclosure in the ’325 Patent, one of ordinary skill in the art would understand the BRI of “active agent” to be “a substance that is intended to provide biological activity.” Ex.

1003, ¶ 67.

VI. EVERY CLAIM OF THE ’325 PATENT FOR WHICH IPR IS REQUESTED IS UNPATENTABLE This petition shows how Ikada, Sakamoto, and/or Schramm anticipate and/or render obvious the Challenged Claims of the ’325 Patent. As detailed below, this petition demonstrates a reasonable likelihood that the Petitioner will prevail with respect to each (and therefore at least one) of the Challenged Claims.

As noted above in Section IV.B., ’325 Patent was allowed based on the Ex- aminer’s belief that the prior art failed to teach the combination of these limitations: (1) the hydrogel is a gelatin; (2) the gelatin has a subunit size when fully hydrated in the range of 0.01 mm to 5 mm; (3) the gelatin has an equilibrium swell from 400% to 5000%; and (4) the hydrogel is present in an applicator.

This petition is based on several prior art references that were neither cited nor made of record during the original application, and that disclose hydrogels that satisfy these very limitations and, therefore, that would have caused the Office to rescind its allowance of the ’325 Patent claims if they had been considered by the

Examiner during the original prosecution. As detailed below, Ikada anticipates claims 1-3, and 6 of the ’325 Patent. See Ex. 1003, ¶¶ 108-109. Sakamoto in view of Schramm renders obvious claims 1-8 of the ’325 Patent. See id., ¶¶ 110-116.

And Ikada in view of Sakamoto renders obvious claims 1-8 of the ’325 Patent. See id., ¶¶ 117-123.

A. Ground 1: Ikada Anticipates Claims 1-3, and 6 Ikada generally describes cross-linked gelatin gel preparations having various levels of “water content” that can be used as sustained release carriers for molecules, such as basic Fibroblast Growth Factor, otherwise known as “bFGF.”

Ex. 1005, 2:1-10; Ex. 1003, ¶ 70-87.

The ’325 Patent characterizes hydrogels in various ways, including through a parameter it calls the “percent swell.” The ’325 Patent defines a hydrogel’s “percent swell” as the difference between the hydrogel’s wet and dry weights, divided by the hydrogel’s dry weight, and multiplied by 100. Id., 11:1-3. Percent swell can be represented in equation form as follows:

ℎ − ℎ = ∗ 100 Eq. (1) ℎ

Id. And, through simple algebra, the ratio of “wet weight” to “dry weight” can be expressed as a function of “percent swell”:

ℎ = +1 Eq. (2) ℎ 100

Importantly, “percent swell” can be correlated to what the patent refers to as

“percent solids” (or “solids content”) of the hydrogel, as shown in Fig. 5 of the

’325 Patent. Similarly, percent swell can also be correlated to the hydrogel’s “water content” or “percent water.” See, e.g., id. 8:34-35 (“A material with 100% hydration will be at its equilibrium water content and fully swollen.”) (emphasis added). “Percent solids” and “percent water” are percentage measures of the dry polymer component and the liquid component, respectively, that make up a hydrogel, and are shown below in annotated Fig. 5 (Ex. 1003, ¶32):

As shown in annotated Fig., 5, the “percent solids” and “percent water” of a hydrogel add to 100% (id., ¶33):

% + % = 100 Eq. (3)

Thus, if either percent solids or percent water of a hydrogel is known, the corresponding “percent swell” can be determined.

“Percent solids” represents that portion of the hydrogel that is made up of the dry polymer and can be determined by dividing the “dry weight” by the “wet weight” of the hydrogel and multiplying by 100 (id., ¶ 34):

ℎ % = = ∗ 100 Eq. (4) ℎ

Conversely, “percent water” represents the liquid portion of the hydrogel, which can be determined by dividing the weight of the hydrogel’s liquid portion by the “wet weight” of the hydrogel and multiplying that ratio by 100 (id., ¶ 35):

ℎ − ℎ % = = ∗ 100 Eq. (5) ℎ

“Percent swell” may be conveyed in terms of “percent solids” or “percent water.” Percent swell as a function of “percent solids” is obtained by rearranging

Equation 4 to solve for the ratio of wet-weight-to-dry-weight (id., ¶ 36):

ℎ 100 = ℎ %

Then, equating the right hand side of the equation above with the right hand side of

Equation 2 results in (id., ¶ 37):

100 = +1 % 100

And solving for “percent swell” results in (id., ¶ 38):

100 = ∗ 100 − 100 Eq. (6) %

Furthermore, expressing “% solids” as “100 - % water” per Equation 3 results in (id., ¶ 39):

100 = ∗ 100 − 100 Eq. (7) 100 − %

Thus, the water content (%) that characterizes the hydrogels disclosed in Ikada can

be correlated to the percent swell of the hydrogels described in the ’325 Patent by

application of Equation 7. Furthermore, solving Equation 7 for “percent water” re-

sults in (Id., ¶ 40):

100 % = 100 − 100 ∗ Eq. (8) 100 +

Applying this equation to the range of equilibrium swells claimed in the ’325 Pa-

tent (i.e., 400% to 5000% (see Claim 1)) allows one to convert the ’325 Patent’s

disclosed 400% to 5000% range into a corresponding range of “percent water” (or

“water content”) of the hydrogel. Based upon this conversion, it is understood that

the ’325 Patent’s range of from 400% to 5000% equilibrium swell is the same as a

percent water (or water content) range of from 80% to 98.0392%. Ex. 1003, ¶ 79.

1. Ikada Anticipates Claim 1 Ikada discloses “[a] fragmented biocompatible hydrogel” as recited in

Claim 1. Ex. 1003, ¶ 109.1.[a]. Specifically, Ikada discloses that “the present in-

vention relates to a crosslinked gelatin gel preparation,” which is a hydrogel. Ex.

1005, 1:8-9; Ex. 1003, ¶ 109.1.[a]. The hydrogels are fragmented, for example, in the form of “spheres or particles.” Id., 3:9-16; see also, id., Table 1 (disclosing gels in particulate form having various average particle diameters). Furthermore, the hydrogels described in Ikada are biocomptabile because they are have “excellent suitability to a living body [and] cause[] almost no stimulation on a living body,”

“free of toxicity to a living body,” and are “excellent in suitability to a living body.” Id.,2:1-5; 2:64-66; 15:54-55.

Ikada further discloses hydrogels that are “at least partially hydrated” and

“substantially free from an aqueous phase,” as recited in Claim 1. Ex. 1003, ¶

109.1.[b]. The term “at least partially hydrated” means that the hydrogels may be either partially hydrated or fully hydrated. In this regard, Example 9 of Ikada, for example, uses 10 mg of crosslinked gelatin gel dry particles capable of achieving a

96% water content when fully hydrated (i.e., hydrated to equilibrium swell). See

Ex. 1005, 9:57-10:6. After drying, the particles of Example 9 of Ikada are immersed in 30 µl of buffer. Id. As explained below, with that amount of buffer, the particles achieve partial hydration.

At full hydration, the 10 mg of crosslinked gelatin gel particles of Example 9

are capable of holding approximately 240 mg of water or aqueous buffer (see Ex.

1003, ¶ 109.1.[b]):

96 % water 10 mg gelatin ∗ = 240 mg water 4 % gelatin

Example 9 discloses hydrating the dry crosslinked gelatin gel particles with

30 µl of buffer, which is approximately 30 mg of buffer (based on the fact that the

density of buffer is approximately equal to that of water) (see id.):

1 ml 1000 mg water 30 μl buffer ∗ ∗ = 30 mg buffer 1000 μl 1 ml water

Because, as explained above, the 10 mg of dry gelatin gel particles of Exam- ple 9 can hold up to 240 mg of water at full hydration, with the addition of 30 mg of buffer, the particles of Example 9 are hydrated to approximately 12.5% of full hydration, and, therefore, they are partially hydrated (see id.):

30 mg of buffer ∗ 100 % = 12.5 % of full hydration 240 mg of buffer (at full hydration)

With respect to the “substantially free from an aqueous phase” limitation

recited in Claim 1, the particles of Ikada’s Example 9 (discussed above) are “par-

tially hydrated” and thus will “not [be] hydrated above [their] capacity to absorb

water” as required by the definition of the phrase “substantially free from an

aqueous phase.” Id. Furthermore, the crosslinked gelatin gels of Ikada are pre-

pared through a water/oil emulsification process that results in particles that are generally uniform in shape, e.g., spherical. See Ex. 1005, 3:39-60. These particles

are generally non-porous and do not generally absorb water through capillary ac-

tion. Ex. 1003, ¶ 109.1.[b]. Because of this, the water absorbed by this type of hy-

drogel diffuses into a polymer network and is not retained in pores through capil-

lary force as a separate phase from the hydrogel. Id.

The hydrogels of Ikada comprise a “gelatin,” as recited in Claim 1 of the

’325 Patent. Id., ¶ 109.1.[c]. In this regard, Ikada states that “the gist of the . . . in-

vention consists in a crosslinked gelatin gel preparation . . . .” Ex. 1005, 1:65-66.

Furthermore, the gelatin hydrogels of Ikada are capable of “absorb[ing] wa-

ter when delivered to a moist tissue target site,” as recited in Claim 1. Ex. 1003, ¶

109.1.[d]. Specifically, as explained above, Example 9 of Ikada discloses partially

hydrated gelatin compositions. Such partially hydrated compositions would neces-

sarily absorb water when delivered to a target site. See id. For example, after addi-

tion of 30 µl of buffer to the dry particles of Example 9 (see id.,9:67-10:3), these particles become partially hydrated, and thus are capable of absorbing further water when delivered to a moist tissue target site due to their hydrophilic nature. See id. ¶¶ 20, 109.1.[d].

Ikada discloses gel particles with “subunit size in the range from 0.01 mm to 5 mm when fully hydrated,” as recited in Claim 1. Id., ¶ 109.1.[e]. The cross-

linked gelatin gel particles of Ikada “have an average particle diameter of 1 to

1,000 µm, and are sieved out to necessary sizes as required depending upon purposes.” Ex. 1005, 4:1-3. Thus, the fully hydrated hydrogels of Ikada have a characteristic width or diameter that falls within that claimed range of subunit size claimed in the ’325 Patent.

Furthermore, Table 1 of Ikada describes, for example, hydrogels prepared in accordance with Example 9 as having an average “particulate” diameter of 30 µm when hydrated to a maximum water content of 96%. Id., Table 1. This 30-µm

(0.03 mm) diameter falls within the claimed range of the ’325 Patent (0.01-5 mm).

Importantly, as explained by Dr. Mooney, particulate diameters in the claimed

range are also disclosed by Ikada even if the 30-µm diameter of Example 9 were to

be understood to correspond to that of a “dry particulate.” Ex. 1003, ¶ 109.1.[e].

This is because a dry particulate having a water content of 96% is capable of ab-

sorbing 24 times its weight in water, resulting in a wet-weight-to-dry-weight ratio

of 25. Id. This ratio can be calculated by application of Equation 7 to determine the

percent swell (2400%) that corresponds to a water content of 96%, and the subse-

quent application of Equation 2, to determine the wet-weight-to-dry-weight ratio

(25) for a percent swell of 2400%:

100 100 % = ∗ 100 − 100 = ∗ 100 − 100 = 2400% 100 − % 100 − 96

ℎ 2400 = +1= +1=25 ℎ 100 100

Because the relative density of water is one, the weight ratio is the same as the volume ratio. Thus, a 25x change in weight translates into a 25x change in volume.

Ex. 1003, ¶ 109. Assuming particulates of spherical shape (which Ikada explicitly discloses), the fully swollen diameter for a dry particle of 30 µm would be approximately 88 µm (0.088 mm), which is also within the claimed range of 0.01 and 5 mm. Id., ¶ 109.1.[e].

Ikada discloses “equilibrium swell” percentages within the range of “400% to 5000%,” as recited in Claim 1. Ex. 1003, ¶ 109.1.[f]. For example, Ikada dis-

closes crosslinked gelatin gel particles with water content ranging from 63.1% to

96.8%. Ex. 1005, Table 1. As explained in Section V.F., the term “equilibrium

swell,” as used in the ’325 Patent, is the “percent swell at equilibrium after the pol-

ymeric material has been immersed in a wetting agent for a time period sufficient

for water content to become constant.” Ex. 1001, 11:9-12. Thus, “percent swell at

equilibrium” may be calculated from percent water content through Equation 7, so

long as the water content is representative of conditions at which the polymeric

material has been immersed in a wetting agent for a time period sufficient for the

water content to become constant. Ex. 1003, ¶ 76, 109.1.[f]. Ikada discloses water

content at equilibrium because the hydrogels of Ikada have been immersed in a

wetting agent for a period sufficient for water content to become constant, as re-

quired by the definition of “equilibrium swell” in the ’325 Patent. See Ex. 1005,

Exs. 1-16 (explicitly stating that the hydrogel particles were allowed to stand in the wetting agent for “a whole day and night” or for “24 hours,” or referring back to a previous example explicitly stating such an immersion period).

By applying Equation 7, as summarized below, several water contents explicitly disclosed in Table 1 of Ikada can be converted into equilibrium swell units, each squarely within the range claimed in the ’325 Patent (400% and 5000%):

Ikada Example Water Content % Equilibrium Swell %

1 95.9 2339

2, 3 95.2 1983

4 92.1 & 95.9 1166 & 2339

5 87.6 & 80.0 706 & 400

6 96.8 3025

7 91.5 1076

9 96.0 2400

10, 11, 12 91.0 1011

13, 14, 15, 16 87.0 669

Ex. 1003, ¶¶ 78, 109.1.[f].

Moreover, as shown in the annotated figure below, the range of equilibrium swell values disclosed in Ikada, 171% (at 63.1% water content) to 3025% (at

96.8% water content), significantly overlaps with the equilibrium swell range claimed in the ’325 Patent.

Ex. 1003, ¶ 79.

Because the ’325 Patent merely claims a range of equilibrium swells without any additional descriptions supporting that this range would be critical for the invention or that there is any difference across the range, such disclosure in the prior art renders such a range unpatentable as anticipated. See MPEP 2131.03(II)

(“PRIOR ART WHICH TEACHES A RANGE OVERLAPPING OR TOUCHING

THE CLAIMED RANGE ANTICIPATES IF THE PRIOR ART RANGE DIS-

CLOSES THE CLAIMED RANGE WITH SUFFICIENT SPECIFICITY”); see also ClearValue Inc. v. Pearl River Polymers Inc., 668 F.3d 1340, 1345 (Fed. Cir.

2012) (holding the claim anticipated because “there is no allegation of criticality or any evidence demonstrating any difference across the range.”).

Ikada inherently discloses hydrogels “being present in an applicator.” Ex.

1003, ¶109.1.[g]. According to Ikada, “the crosslinked gelatin gel in the form of spheres or particles may be used for the administration by injection.” Ex. 1005,

3:14-16 (emphasis added); see also id., 18:49-51. To be administered by injection, the hydrogels of Ikada must necessarily be present in an applicator such as a syringe or other similar device. Ex. 1003, ¶109.1.[g].

Accordingly, Ikada anticipates Claim 1.

2. Ikada Anticipates Claim 2 Ikada discloses hydrogels “having an in vivo degradation time of less than one year,” as recited in Claim 2 of the ’325 Patent. Ex. 1003, ¶109.2. The crosslinked gelatin of Ikada is “a natural polymer that can undergo in vivo degradation and absorption . . . .” Ex. 1005, 1:58-60. Furthermore, Figures 3 and 7 disclose residual weight of the hydrogel as a function of time in vivo, corresponding to degradation times less than 15 days. Id., Figs. 3, 7.

Accordingly, Ikada anticipates Claim 2.

3. Ikada Anticipates Claim 3

Ikada discloses hydrogels that are “at least partially hydrated with an aque-

ous medium comprising an active agent,” as recited in Claim 3. Ex. 1003, ¶109.3.

As explained above, Ikada discloses hydrogels that are at least partially hydrated.

See Section V1.A.1. Ikada further teaches the use of those partially hydrated hy-

drogels for delivering basic Fibroblast Growth Factor (bFGF), which is an active

agent used, for example, for the proliferation of a variety of cell types, as well as

fibroblast. Ex. 1005, 1:13-23. Specifically, Ikada teaches incorporating bFGF into

crosslinked gelatin gels by dropwise addition of a bFGF aqueous solution to the

crosslinked gelatin gel. Id., 4:60-65, Exs. 1, 5-8, 10, 13, 14.

Accordingly, Ikada anticipates Claim 3.

4. Ikada Anticipates Claim 6 Ikada discloses “a method for delivering an active agent to a patient,”

where the method comprises “administering to a target site on the patient an

amount of the hydrogel” of the type claimed in Claim 3, as recited in Claim 6. Ex.

1003, ¶ 109.6. Ikada discloses that bFGF-containing crosslinked gelatin gel com-

positions can be subcutaneously implanted into back portions of mice (Ex. 1005,

Test Ex. 1) and cut portions of rat fibula (id., Test Ex. 10). See also id., Test Ex.9

(disclosing injecting gelatin gel particles impregnated with bFGF into a rat ilium).

Accordingly, Ikada anticipates Claim 6.

B. Ground 2: Sakamoto in View of Schramm Renders Obvious Claims 1-8

Sakamoto discloses a biodegradable hemostatic agent made of a polymeric

material of which gelatin, collagen, and chitin polymers are described as particular-

ly favorable. Ex. 1006, 3:48-53. Sakamoto characterizes the swelling of this hemo-

static material as it absorbs water from its surrounding using a parameter referred

to as the “water absorption capability.” See id., 33-45. Like the “percent swell” described in the ’325 Patent, “water absorption capability” is determined by calculating the difference between the material’s wet and dry weights, divided by the material’s dry weight, and multiplied by 100. See id. Sakamoto discloses the “water absorption capability” formula as follows:

Id., 3:40-45.

Sakamoto teaches a wide range of “water absorption capabilities” and states

that the “[b]iodegradable material according to this invention should have a water-

absorption capability of about 50 weight percent or more” and that “a preferable

water-absorption capability is less than 1000 weight percent.” Id., 3:33-37. As

shown in the figure below, Sakamoto’s “water absorption capability” overlaps by

at least 600 percentage points (i.e., from 400% to 1000%) with the ’325 Patent’s

claimed “equilibrium swell range.” Ex. 1003, ¶ 112.

The “wet weight” in the “water absorption capability” formula in Sakamoto is determined after three minutes of soaking. See Ex. 1006, 3:40-45. The “wet weight” for the percent swell at equilibrium claimed in the ’325 Patent is determined after the hydrogel material “has been immersed in a wetting agent for a time period sufficient for water content to become constant,” in accordance with the definition of equilibrium swell. See Section V.F.

Importantly, a person of ordinary skill in the art would understand that at

three minutes, the polymers of Sakamoto would be essentially at full hydration

(i.e., at equilibrium). Ex. 1003, ¶ 93, 116.1.[f]. This is because the types of materi-

als, such as crosslinked gelatin (e.g., Gelfoam), disclosed in Sakamoto are highly

hydrophilic and achieve equilibrium swell rapidly. Thus, the bulk of water would

be absorbed by these types and forms of materials within three minutes. Id., ¶¶ 20,

93. Sakamoto makes this evident by disclosing water absorption capabilities that

ensure transformation into an “injectable sol-form promptly, . . . within 2-3 minutes.” Ex. 1006, 3:33-37 (emphasis added). This prompt water absorption oc-

curs because the hydrogel particles in the sol disclosed in Sakamoto absorb water

within 3 minutes. Ex. 1003, ¶¶ 93, 116.1.[f]. Furthermore, as explained by Dr.

Mooney, this rapid absorption of liquid by the hydrogel particles disclosed in Sa- kamoto is further confirmed from first principles. Id., ¶¶ 116.1.[f]. The diffusion coefficient of water into a crosslinked gelatin is approximately 2 cm2/second, thus,

the Gelfoam particles in the size range of 20 µm to 200 µm disclosed by Sakamoto

absorb water within seconds. Id. (concluding that water absorption would occur in less than 1 second for 20- µm particles and within 20 seconds for 200- µm particles). But the distinction in “soaking” or “immersion” time between Sakamoto and the ’325 Patent notwithstanding, Sakamoto clearly teaches the same concept as

“equilibrium swell” claimed by the ’325 Patent—determining how much water can be taken up by a hydrogel and also that such amount can be varied. Id., ¶¶ 93,

116.1.[f].

In addition to disclosing gelatin polymers as suitable hemostatic materials,

Sakamoto specifically describes Gelfoam powder as a “biodegradable gelatin powder” from Upjohn that has “water-absorption capability of 500-800 weight percent” and is a “mixture of flake substance in its longest dimension from 20 µm to

200 µm.” Ex. 1006, 5:45-47. Sakamoto further states that the combination of Gel- foam powder, distilled water, thrombin, and Factor XIII was used to make a “gel- formed hemostatic agent” and was applied via a syringe with a needle to bleeding rat livers and hemostasis was achieved. Id., 5:45-6:5 (emphasis added).

Like Sakamoto, the Schramm reference also discloses use of the fragmented,

biocompatible, cross-linked hydrogel, Gelfoam. Ex. 1003, ¶¶ 101-107. Schramm

teaches use of a Gelfoam powder paste as an injection for vocal cord paralysis. Ex.

1007, p. 1268. Schramm states that “Gelfoam® was developed as a hemostatic ma-

terial,” that “tissue tolerance has been excellent” for the material, and when it is

placed in muscle, “it remains for 2 to 5 weeks.” Id., p. 1269. Schramm provides

photographs showing the Gelfoam paste inserted into a syringe and being extruded

through a needle. Id., Figs. 1-3.

Schramm also teaches use of a syringe to apply a hemostatic gel. For exam-

ple, Schramm teaches preparation of a 5 cc gelatin paste that “is placed into the

open barrel of a 5 cc syringe and then injected into the Arnold-Brunings injection

system(Fig. 1). The viscosity of the Gelfoam paste is nearly the same as that of

Teflon paste, and since the material is cohesive when injected through a needle, the

Teflon injection technique with the Arnold-Brunings system may be used (Figs. 2 and 3).” Ex. 1007, p. 1269. The Schramm also show the Gelfoam paste present in a syringe (Fig. 1) and also being extruded through an 18 gauge needle (Fig. 2). Id.,

Fig. 1,2.

1. Motivation to Combine Sakamoto and Schramm A person of ordinary skill in the art would have been motivated to combine

the teachings of Sakamoto with Schramm to arrive at the invention claimed in the

’325 Patent. See Ex. 1003, ¶¶ 111-115. Specifically, Sakamoto and Schramm each disclose crosslinked hydrogels formed by the addition of water (or an aqueous solution, e.g., saline) to Gelfoam powder that are used as hemostatic agents. A person of skill in the art in view of Sakamoto would have been motivated to explore the wide range of concentrations disclosed in Sakamoto (50-500 mg/ml) to test different consistencies. See id., ¶ 100. In disclosing that the preferred form of the hemostatic material is in sol form, Sakamoto states that a “[r]eason[] why such hemo- statics [sols] have not so far been produced is that, according to the general theo- ries of hemostatic therapy, it is better to use hemostatic materials in the dry state, or that it is necessary to apply strong compression to the bleeding site.” Ex. 1006,

2:19-21. More particularly, for a crossslinked gelatin powder like Gelfoam, at the low end of the concentrations disclosed in Sakamoto the result is a sol in which the dispersed medium is hydrogel particles in water (or aqueous solution). Ex. 1003, ¶

100. On the other hand, at the mid-to-high concentrations, the result is a hydrogel in which the dispersed medium is water (or aqueous solution) in a polymer network. Id., ¶¶ 100, 115. This range of concentrations and resulting forms is shown in the figure below. Id., ¶ 100,

Schramm provides motivation to one of ordinary skill in the art to use a material that is not a sol, but rather one where “[t]he viscosity of the Gelfoam paste is

. . . cohesive when injected . . . .” Ex. 1007, p. 1269. In other words, Schramm provides motivation to ensure that the material is only hydrated to a point (e.g., partially hydrated) where it exists in a paste form (i.e., it is not dry), but where it is not so hydrated that it is in a “sol” form with excess water. See Ex. 1003, ¶ 115. Thus, a person of ordinary skill in the art working in developing hemostatic materials or methods would have been motivated to combine the teachings of Schramm with

Sakamoto to arrive at the claimed invention. Id.

The claimed invention in the ’325 Patent is essentially the use of Gelfoam or

Gelfoam-like gelatin gel particles in the precise manner that the particles were used in Sakamoto and described in Schramm—i.e., as hemostatic agents. Sakamoto shows that it was well known to combine Gelfoam powder with thrombin, to put that combination in a syringe, and to apply it for use as a hemostatic agent. Moreo-

ver, Sakamoto characterizes its disclosed hemostatic materials in the precise manner in which the ’325 Patent characterizes its claimed material—through the use of a swelling measure. Importantly, the water absorption capability of Sakamoto is used to characterize hydrogels, not sols. Ex. 1003, ¶ 93. Thus, regardless of whether the overall Gelfoam system disclosed in Sakamoto is a sol (at the low end of the concentration range) or a hydrogel (at the mid-to-high end of the concentration range), the “water absorption capability” parameter is used to characterize the hydrogel component of the preferred embodiments (sol) disclosed in Sakamoto. Id.

2. Sakamoto in View of Schramm Renders Claim 1 Ob- vious Sakamoto and Schramm both disclose “[a] fragmented biocompatible hy-

drogel” as recited in Claim 1. Ex. 1003, ¶ 116.1.[a]. Specifically, Sakamoto discloses the preparation and use of Gelfoam, which (as explained in Section IV.C.) is a biodegradable gelatin powder that forms a hydrogel when mixed with water or an aqueous solution. Id.; Ex. 1006, 5:45-47. In this regard, Sakamoto explains that the

Gelfoam mixture made in accordance with Example 1 resulted in a “gel-formed hemostatic agent.” Id., 6:3. The Gelfoam hydrogel of Sakamoto is fragmented

(i.e., it is in the form of discrete subunits) because it is in powder form. And more precisely, it is in the form of flakes with “longest dimension from 20 µm to 200

µm.” Id., 5:45-47; see also id., 3:54-57 (“For the carrier of the flake type used in this invention, the longer dimension is generally about 5000 microns or less. . . ”).

The hydrogel of Sakamoto is also biocompatible and biodegradable, i.e., it has the

“property of being absorbed into the living tissue so that there is no necessity of further action such as removal thereof after the initial application to the affected site.” Id., 3:48-50. Schramm discloses the use of Gelfoam powder, which is frag-

mented and exhibited “minimal tissue reaction.” Ex. 1007, p . 1269. Furthermore

Schramm discloses the preparation of Gelfoam powder mixed with saline, which

would create a hydrogel. Id.

Ethicon is not contending in this IPR that Sakamoto explicitly describes a

hydrogel that is “at least partially hydrated” and “substantially free from an

aqueous phase,” as recited in Claim 1. Ex. 1003, ¶116.1.[b]. However, it would

have been obvious to one having ordinary skill in the art that such a level of hydra-

tion could be achieved with a gelatin gel such as Gelfoam. See id. Indeed,

Schramm demonstrates that Gelfoam could be mixed with an amount of aqueous

solution that resulted in a cohesive paste that is both partially hydrated and sub-

stantially free from an aqueous phase. Id. Specifically, as prepared in Schramm,

Gelfoam powder is at least partially hydrated. Ex. 1007, p. 1269 (“One gram of

Gelfoam powder is placed in a dish and 4.0 cc of saline is added slowly while mix-

ing constantly.”). According to the equilibrium swell equation disclosed in the ’325

Patent, for a given equilibrium swell, the water content at equilibrium hydration

can be determined by solving Equation 1 for the difference between wet weight and dry weight as follows:

ℎ − ℎ = ℎ

ℎ = ∗ 100

As described in Sakamoto, Gelfoam powder has a water absorption capability between 500-800 weight percent. This is an inherent property of Gelfoam powder.

Ex. 1003, ¶ 116.1.[b]. Applying the lower end of the water absorption capability of

Gelfoam powder (i.e., 500%), the corresponding weight of water at equilibrium for

Gelfoam powder is:

1000 ℎ = 500 ∗ = 5000 100

As mentioned above, Schramm discloses using 1000 mg of Gelfoam powder in 4

cc of saline. Ex. 1007, p. 1269. Thus, because the density of saline is approximate-

ly equal to that of water, the mass of saline added to Gelfoam powder is 4000 mg

(Ex. 1003, ¶ 116.1.[b]):

1000 4 ∗ = 4000 1

At this concentration, the Gelfoam particles disclosed in Schramm are not hydrated

to their equilibrium hydration. Instead, based on the swell percent at equilibrium

derived from Gelfoam’s water absorption capability of 500%, the Gelfoam particles are hydrated to approximately 80.0%, i.e., they are partially hydrated (see id.):

ℎ 4000 ∗ 100 = ∗ 100 = 80% ℎ 5000

The same conclusion is also reached if instead of using the lower end (i.e.,

500%) of the water absorption capability of Gelfoam disclosed in Sakamoto, the

upper end (i.e., 800%) is applied. See id. In this case, the corresponding weight of water at equilibrium for Gelfoam powder is:

1000 ℎ = 800 ∗ = 8000 100

At a water absorption capability of 800%, the Gelfoam particles disclosed in

Schramm are similarly not hydrated to their equilibrium hydration. Instead, based on the swell percent at equilibrium derived from Gelfoam’s water absorption capability of 800%, the Gelfoam particles would be hydrated to approximately 50%, i.e., they are partially hydrated (see id.):

ℎ 4000 ∗ 100 = ∗ 100 = 50% ℎ 8000

With respect to the “substantially free from an aqueous phase” limitation

recited in Claim 1, the Gelfoam compositions disclosed in Schramm (and de-

scribed above) are also necessarily substantially free from an aqueous phase by vir-

tue of being partially hydrated, in accordance with the proposed definition of sub-

stantially free from an aqueous phase (i.e., “fully or partially hydrated, but not hydrated above its capacity to absorb water.”). Ex. 1003, ¶ 116.1.[b]. Qualitative confirmation that the Gelfoam material (at the concentration disclosed in

Schramm) is substantially free from an aqueous phase can be found in Figure 2 of

Schramm, which shows the disclosed Gelfoam paste does not separate into two phases when force is applied to extrude it from a syringe, and instead, “[t]he viscosity of the Gelfoam paste is . . . cohesive when injected . . . .” Ex. 1007, p. 1269-

1270 (emphasis added):

The hydrogel of Sakamoto comprises a “gelatin,” as recited in Claim 1. Ex.

1003, ¶ 116.1.[c]. Specifically, Sakamoto discloses that “[p]referable materials for

this purpose include collagen, gelatin, chitin . . . . Gelatin, collagen and chitin are

especially favorably used.”) (emphasis added); Ex. 1006, 3:51-53. More particular-

ly, Sakamoto discloses using Gelfoam powder in Example 1 (see id., 5:45), which

was a well-known gelatin powder at the time of the invention.

And even if Sakamoto is unclear on whether it explicitly describes a hydro-

gel that is capable of “absorb[ing] water when delivered to a moist tissue target

site,” as recited in Claim 1, it would have been obvious to one having ordinary skill

in the art that a partially hydrated hydrogel necessarily absorbs water when deliv-

ered to a moist tissue. Ex. 1003, ¶ 116.1.[d]. As discussed above, the gelatin parti-

cles disclosed Schramm are partially hydrated. Indeed, water absorption is an in-

herent property of partially hydrated crosslinked gelatin powders such as Gelfoam,

so the partially hydrated gelatin particles disclosed in Schramm are capable of ab-

sorbing water when delivered to a moist tissue target site. Id.

Sakamoto further discloses gel particles with “subunit size in the range

from 0.01 mm to 5 mm when fully hydrated,” as recited in Claim 1. Ex. 1003, ¶

116.1.[e]. Example 1 of Sakamoto discloses that the Gelfoam powder was a “mix-

ture of flake substance in its longest dimension from 20 µm to 200 µm.” Ex. 1006,

5:45-47; see also 3:20-24. Notably, even if the particle sizes disclosed in Sakamoto

are interpreted to refer to particle sizes in the dry state, the particle sizes still fall

within the claimed 0.01 mm to 5.0 mm range when fully hydrated because Sa-

kamoto discloses administration of hydrated particles through syringes with extru-

sion orifices that would require a particle size smaller than the upper limit of the

claimed range. Ex. 1003, ¶ 116.1.[e].

Sakamoto discloses “equilibrium swell” percentages within the range of

“400% to 5000%,” as recited in Claim 1. Ex. 1003, ¶ 116.1.[f]. Sakamoto teaches

measuring water-absorption capability by use of the formula:

Ex. 1006, 3:41-46. As previously explained, this formula is similar to the formula for calculating equilibrium swell that is disclosed in the ’325 Patent. See Ex. 1001,

21:19-21. The difference between these two formulas is that the water-absorption capability in Sakamoto uses the weight of water that is absorbed after soaking for three minutes, while the ’325 Patent describes a water content that is reached by soaking the particles for a time period “sufficient for water content to become constant.” Compare Ex. 1006, 3:41-46 with Ex. 1001, 11:9-12).

The hemostatic composition of Example 1 made from Gelfoam powder in

Sakamoto is disclosed as having a “water-absorption capability of 500 - 800 weight percent.” Ex. 1006, 5:45-46. Although this weight percent was apparently determined after soaking Gelfoam powder for three minutes at 25º C, a person of ordinary skill in the art would understand that the bulk of the water would be absorbed by a crosslinked gelatin gel within three minutes based on the diffusion time of water into a crosslinked polymer. Ex. 1003, ¶ 116.1.[f]; see also Ex. 1019, p. 51; Ex. 1020, p. 14.

Thus, because the equilibrium swell range disclosed by Sakamoto either overlaps or is within the range claimed by the ’325 Patent—and because the ’325

Patent merely claims a range of equilibrium swells without any additional descrip-

tions supporting that this range would be critical for the invention or that there is any difference across the range—Sakamoto discloses this claim limitation. See

MPEP 2103.03(II); see also ClearValue, 668 F.3d at 1345 (Fed. Cir. 2012). Alter-

natively, Sakamoto’s disclosed water absorption range renders the recited equilib-

rium swell range of the ’325 Patent obvious because “[i]n the case where the

claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima fa-

cie case of obviousness exists.” MPEP 2144.05(I); see also in re Geisler, 116 F.3d

1465, 1469-71 (Fed. Cir. 1997) (upholding Patent Office’s obviousness rejection because applicant failed to establish the claimed range exhibited unexpected properties to rebut the prima facie case of obviousness.)

Sakamoto discloses hydrogels “being present in an applicator.” Ex. 1003, ¶

116.1.[g]. According to Sakamoto, “[t]he hemostatic agent of this invention is usually filled in a vial and an ampule made of glass or plastic material which are available for packing of medicine, and…at the time of use, it is used by suction in- to a syringe.” Ex. 1006, 5:22-24; see also id., 5:32-34 (describing difficulty of injecting a sol with a concentration above disclosed range), 6:1-4 (describing extrusion of “gel-formed hemostatic agent” from a syringe).

Accordingly, for the reasons set forth above, Sakamoto in view of Schramm renders claim 1 obvious. See Ex. 1003, ¶ 116.1.

3. Sakamoto in View of Schramm Renders Claim 2 Ob- vious

Sakamoto discloses hydrogels “having an in vivo degradation time of less than one year,” as recited in Claim 2. Ex. 1003, ¶ 116.2. In particular, the type of gelatin hydrogel, such as Gelfoam, disclosed in Sakamoto is a “carrier material constituting the hemostatic agent” having a biodegradable property of “being absorbed into the living tissue so that there is no necessity of further action such as removal thereof after the initial application to the affected site.” Ex. 1006, 3:48-50.

Schramm further explains that Gelfoam “[a]bsorption is gradual over a period of six to ten weeks, allowing time for some glottis compensation.” Ex. 1007, p. 1268.

Accordingly, Sakamoto in view of Schramm renders claim 2 obvious.

4. Sakamoto in View of Schramm Renders Claims 3, 4, and 5 Obvious Sakamoto discloses hydrogels that are “at least partially hydrated with an aqueous medium comprising an active agent,” as recited in Claim 3. Ex. 1003, ¶

116.3. As explained in the context of Claim 1 above, Sakamoto in view of

Schramm teaches a partially hydrated hydrogel. Furthermore, Claim 4 recites that the active agent should be a “clotting agent” and Claim 5 recites that the clotting agent is “thrombin.” Id., ¶ 116.4-5. In this regard, Sakamoto reports that the hydrogels it discloses, including gelatin, “can be mixed with Factor XIII and thrombin for dissolution, and carrier is treated by the resultant solution and, as a result,

Factor XIII and thrombin can be adsorbed physically.” Ex. 1006, 4:40-41. Fur- thermore, Example 1 of Sakamoto uses an aqueous solution consisting of thrombin

and Factor XIII to hydrate the gelatin (Gelfoam) powder. See id., 5:45-51. Sa- kamoto also teaches the use a hemostatic agent containing thrombin alone with no

Factor XIII. Id., Table 1 (Comparative Examples 3-4).

Accordingly, Sakamoto in view of Schramm renders Claims 3, 4, and 5 obvious.

5. Sakamoto in View of Schramm Renders Claim 6 Ob- vious

Sakamoto discloses “a method for delivering an active agent to a patient,”

where the method comprises “administering to a target site on the patient an

amount of the hydrogel” of the type claimed in Claim 3, as recited in Claim 6. Ex.

1003, ¶ 116.6. Specifically, Sakamoto discloses delivering thrombin and Factor

XIII to a bleeding site by fixing the active agents to a carrier hydrogel. See Ex.

1006, 4:57-5:3. Furthermore, thrombin and Factor XIII is delivered to a female rat

by administering to the site of hepatic biopsy an amount of gelatin hydrogel con-

taining the active agents. See id., 5:45-51. Additionally, comparative Examples 3-4 in Table 2 of Sakamoto demonstrate hemostasis with a hemostatic agent containing thrombin. See id., 7:33-34.

Accordingly, Sakamoto in view of Schramm renders Claim 6 obvious.

6. Sakamoto in View of Schramm Renders Claim 7 Ob- vious

Sakamoto discloses a “method for delivering a clotting agent to a patient,”

as recited in Claim 7. Ex. 1003, ¶ 116.7. As explained with respect to Claim 6, Ex-

ample 1 of Sakamoto describes delivery of thrombin and Factor XIII to a female

rat by administering to the site of hepatic biopsy an amount of gelatin hydrogel

containing the active agents (thrombin and Factor XIII). See id., 5:45-51. Claim 7 also requires that the claimed method comprise “administering from the applicator to a bleeding target site an amount of the hydrogel of claim 4 sufficient to inhibit bleeding. In this regard, Sakamoto discloses the application of the “gel- formed hemostatic agent” made from Gelfoam powder through the use of an applicator—in this case a syringe with a biopsy needle. Id., 5:58-6:3. From the time of application of the hemostatic agent, hemostasis (i.e., inhibition of bleeding) was observed at various time intervals. Id., 6:3-5.

Accordingly, Sakamoto in view of Schramm renders Claim 7 obvious.

7. Sakamoto in View of Schramm Renders Claim 8 Ob- vious Sakamoto discloses a “method for delivering thrombin to a patient,” as recited in Claim 8. Ex. 1003, ¶ 116.8. As explained with respect to Claim 7, Example

1 of Sakamoto describes delivery of active agents to a subject. One of the active agents of Example 1 is thrombin. Ex. 1006, 5:54-58. Claim 7 also requires that the claimed method comprise “administering from the applicator to a bleeding target site an amount of the hydrogel of claim 5 sufficient to inhibit bleeding. As ex-

plained with respect to Claim 7, Sakamoto discloses the application of the “gel- formed hemostatic agent” through a syringe, and hemostasis was observed following the infusion. Id., 5:54-6:5.

Accordingly, Sakamoto in view of Schramm renders claim 8 obvious.

C. Ground 3: Ikada in view of Sakamoto Renders Obvious Claims 1-8

1. Motivation to Combine Ikada and Sakamoto One of ordinary skill in the art would have been led to combine the teachings of Ikada with Sakamoto to arrive at the claimed invention of the ’325 Patent.

See Ex. 1003, ¶¶ 118-123. Ikada and Sakamoto are each related to particulate

fragmented biocompatible hydrogel materials that are used as drug delivery mate-

rials. In the case of Ikada, it is delivery of basic Fibroblast Growth Factor (bFGF)

and in Sakamoto it is thrombin and/or Factor XIII. A person of skill in the art

working on the delivery of such materials as discussed in Ikada would be motivat-

ed by the disclosures in Ikada and Sakamoto to use the Ikada gelatin hydrogel ma-

terials for delivery of thrombin for use in hemostatic applications. Id., ¶ 118.

Ikada makes clear in its discussion of the “prior art” that its invention relates to “sustained release preparation of physiologically active peptides and proteins.”

Ex. 1005, 1:33-41. Although Ikada focuses on bFGF, the reference notes that bFGF is “like other polypeptides and proteins.” Id., 1:24-26. Thus, one of ordinary

skill in the art working on the delivery of thrombin (a protein) as described in Sa- kamoto, would be motivated to look to the teachings of Ikada. See Ex. 1003, ¶ 118.

As previously explained, the claimed invention in the ’325 Patent is the use of gelatin gel particles in the precise manner that the particles were used in the pri- or art—i.e., in combination with thrombin for use as hemostatic agents. Sakamoto shows that it was well known to combine gelatin hydrogel materials (e.g., Gel- foam) with thrombin, to put that combination in a syringe, and to apply it for use as a hemostatic agent. One of skill in the art would have been motivated in view of that teaching and the teaching of Ikada to make the simple substitution in the Ikada materials to deliver thrombin, instead of bFGF, using the gelatin hydrogel materials that are described there. Id., ¶ 118.

To the extent it is determined that Ikada does not teach the equilibrium swell characteristics of the ’325 Patent claims, one of ordinary skill in the art would have found it obvious to arrive at an equilibrium swell as claimed, and one of ordinary skill in the art would have had a reasonable expectation of success in doing so. Id.,

¶ 119. In fact, Sakamoto expressly recognizes that varying “water absorption capabilities” may be necessary. For example, Sakamoto states that “[b]iodegradable material according to this invention should have a water-absorption capability of about 50 weight percent or more. . . . On the other hand, a preferable water- absorption capability is less than 1000 weight percent, and that less than 500

weight percent is more preferable.” Ex. 1006, 3:33-37. Thus, Sakamoto teaches a

range of “water-absorption capabilities”—i.e., equilibrium swell values—that at

least overlap with the 400%-5000% range claimed in the ’325 Patent.

It was also well known to one of ordinary skill in the art that, other things

equal, increasing the cross-linking of a hydrogel would lower its equilibrium swell.

This concept was known to anyone working in the field of swellable polymers at

the time of the invention. Ex. 1003, ¶ 120. In fact, Ikada teaches how to vary the

water content of the crosslinked gelatin gel by varying the amount of crosslinking.

In this regard, Ikada teaches that:

The crosslinked gelatin gel can be arranged to have a desired water content by varying the concentrations of the gelatin as a raw material and the crosslinking agent. For increasing the water content, both the gelatin concentration and the crosslinking agent concentration are de- creased. For decreasing the water content, conversely, both the gelatin concentration and the crosslinking agent concentration are increased.

Ex. 1005, 4:52-59.

Thus, for at least the reasons discussed above, a person of ordinary skill in

the art would have been motivated to apply the teachings of Sakamoto with respect

to the gelatin hydrogel materials disclosed in Ikada.

1. Ikada in View of Sakamoto Renders Claim 1 Obvious As explained in detail in Section VI.A.1., supra, Ikada discloses all the limi-

tations recited in Claim 1. Both Sakamoto and Ikada disclose “a fragmented bio-

compatible hydrogel.” Ex. 1003, ¶ 123.1.[a]. The invention in Ikada relates to

“crosslinked gelatin gel preparation,” which is a hydrogel. Ex. 1005, 3:9-16; Ex.

1003, ¶ 123.1.[a]. The crosslinked gelatin gel preparations described in Ikada are

“fragmented” because they may be in particle form. Id., 3:9-16. Furthremore, Ta- ble 1 discloses the average particle diameter for gelatin gels in particulate form.

Id., Table 1. The gelatin gel described in Ikada is “biocompatible” because it has

“excellent suitability to a living body, causes almost no stimulation on a living body.” Id., 2:1-5; see also Id., 2:64-66, 15:54-55. As explained in detail above

(Section VI.B.1., supra) and in the claim chart (Ex. 1003, ¶ 123.1.[a]) , Sakamoto discloses the preparation and use of Gelfoam powder, which is a biocompatible gelatin powder (i.e., fragmented) that forms a hydrogel when mixed with water or an aqueous solution. Specifically, The hydrogel of Sakamoto is also biocompatible and biodegradable, i.e., it possesses the “property of being absorbed into the living tissue so that there is no necessity of further action such as removal thereof after the initial application to the affected site.” Id., 3:48-50. Example 1 uses Gelfoam

powder, which is fragmented, because it is in powder form and is described as in

the form of flakes with “longest dimension from 20 µm to 200 µm.” Id., 5:45-47.

Furthermore, the Gelfoam powder disclosed in Sakamoto is capable of absorbing water when mixed with an aqueous solution, and thus is a hydrogel. Id., 3:11-12,

5:31-34, 5:58-6:1, 6:3.

Ikada discloses hydrogels that are “at least partially hydrated.” Ex. 1003, ¶

123.1.[b]. As explained in detail above (Section VI.A.1., supra) and as calculated

in the claim chart (Ex. 1003, ¶ 123.1.[b]), the crosslinked gelatin gel particles of

Example 9, in which 10 mg of crosslinked gelatin gel particles are hydrated with

30 µl of buffer, are partially hydrated to a “percent water” of 12.5 % because the

gelatin material is capable of absorbing 240 mg of water. Id. Because these parti-

cles are partially hydrated, they are also “substantially free from an aqueous

phase.” Furthermore, Ikada discloses preparation of cross-linked gelatin gels

through a water/oil emulsification process (Ex. 1005, 3:39-60), which would result

in non-porous particles that do not absorb water through capillary action (Ex. 1003,

¶ 123.1.[b]). Although, Ethicon is not contending in this IPR that Sakamoto ex-

plicitly describes a hydrogel that is “at least partially hydrated” and “substantially

free from an aqueous phase,” it would have been obvious to one having of ordi-

nary skill in the art that such a level of hydration could be achieved with a cross-

linked gelatin gel such as Gelfoam. See id., ¶ 123.

Ikada and Sakamoto disclose hydrogels that comprise “gelatin.” Ex. 1003, ¶

123.1.[c]. Ikada explicitly states that “the present invention consists in a cross-

linked gelatin gel preparation . . . .” Ex. 1005, 1:65-66 (emphasis added). Sakamo-

to discloses gelatin as one of the preffered materials for use in the invention. Ex.

1006, 3:51-53. Furthermore, Example 1 of Sakamoto discloses the use of Gelfoam

powder (see id.,5:45), which was a well-known crosslinked gelatin powder at the time of the invention. Ex. 1003, ¶ 123.1.[c].

The compositions disclosed in Ikada “will absorb water when delivered to a moist tissue target site.” Id., ¶ 123.1.[d]. Water absorption is an inherent property of partially hydrated crosslinked gelatin powders. As explained above, Ikada discloses hydrogles that are partially hydrated, and thus will absorb water when delivered to a moist tissue target site. For example, after addition of 30 µl of buffer to the dry particles of Example 9 of Ikada, these particles become partially hydrated and will absorb further water when delivered to a moist tissue target site. See Ex.

1005, 9:67-10:3. And while Sakamoto does not appear to explicitly describe a hy-

drogel that is capable of “absorb[ing] water when delivered to a moist tissue target

site,” as recited in Claim 1, it would have been obvious to one having ordinary skill

in the art that a partially hydrated hydrogel necessarily absorbs water when deliv-

ered to a moist tissue. Ex. 1003, ¶ 121.

Ikada and Sakamoto disclose crosslinked gelatin gel particles that “have an

average particle diameter of 1 to 1,000 µm, and are sieved out to necessary sizes

as required depending upon purposes.” Ex. 1003, ¶ 123.1.[e]. As explained in de-

tail above (Section VI.A.1., supra) and in the claim chart (Ex. 1003, ¶ 123.1.[e]),

the fully hydrated hydrogels of Ikada have a characteristic width or diameter that

falls within the claimed range of subunit sized claimed in the ’325 Patent. Particu-

late diameters in the claimed range are also disclosed by Ikada even if the 30-µm diameter of Example 9 is understood to correspond to that of a “dry particulate.”

Id., ¶ 123.1.[e]. This is because a dry particulate having a water content of 96% is capable of absorbing 25 times its weight in water. Id. Furthermore, Sakamoto discloses that the Gelfoam powder was a “mixture of flake substance in its longest dimension from 20 µm to 200 µm.” See also Ex. 1006, 3:20-24.

Ikada and Sakamoto discloses “equilibrium swell” percentages within the range of “400% to 5000%.” Id., ¶ 123.1.[f]. As explained in detail above (Section

VI.A.1., supra) and as calculated in the claim chart (Ex. 1003, ¶ 123.1.[f]), Ikada discloses crosslinked gelatin gel particles with water content ranging from 63.1% to 96.8% at full hydration (i.e., at equilibrium) (Ex. 1005, Table 1), which correspond to an equilibrium swell range of 171% to 3025%. Similarly, Example 1 of

Sakamoto describes the preparation and use of a hemostatic composition made from Gelfoam powder, which has a “water-absorption capability of 500 - 800 weight percent.” Id., 5:45-46. Although water-absorption capability is assessed at

3 minutes after immersion in wetting agent, a person of ordinary skill in the art would understand that based on the diffusion properties of the gelatin composition that the bulk of the water would be absorbed by a crosslinked gelatin gel within three minutes, such that the water content has become constant as required for the

term “equilibrium swell.” Ex. 1003, ¶ 123.1.[f]. In addition, Sakamoto discloses

hydrogels with water-absorption capabilities between 50-1000% (Ex. 1006, 3:33-

37), which fall within the claimed equilibrium swell range.

Therefore, the equilibrium swell range disclosed in Ikada and Sakamoto significantly overlaps with the equilibrium swell range claimed in the ’325 Patent.

Because the ’325 Patent merely claims a range of equilibrium swells without any additional descriptions supporting that this range would be critical for the invention or that there is any difference across the range, such disclosure in the prior art renders such a range unpatentable as anticipated. See MPEP 2131.03(II); see also

ClearValue, 668 F.3d 1340 at 1345 (Fed. Cir. 2012).

Ikada and Sakamoto disclose hydrogels “being present in an applicator.”

Ex. 1003, ¶ 123.1.[g]. According to Ikada, “the crosslinked gelatin gel in the form

of spheres or particles may be used for the administration by injection . . . .” Ex.

1005, 3:14-16.; see also id., 18:49-51. To be administered by injection, the hydrogels of Ikada must necessarily be present in an applicator such as a syringe or other similar device. Ex. 1003, ¶ 123.1.[g]. Sakamoto also discloses hydrogels “being present in an applicator.” Ex. 1003, ¶ 123.1.[g]. According to Sakamoto, “[t]he hemostatic agent of this invention is usually filled in a vial and an ampule made of glass or plastic material which are available for packing of medicine, and…at the time of use, it is used by suction into a syringe. Ex. 1006, 5:22-24; see also id.,

5:32-34, and 6:1-4 (describing extrusion of “gel-formed hemostatic agent” from a syringe). Accordingly, Ikada in view of Sakamoto renders Claim 1 obvious.

2. Ikada in View of Sakamoto Renders Claim 2 Obvious Both Ikada and Sakamoto disclose hydrogels “having an in vivo degrada-

tion time of less than one year,” as recited in Claim 2. See Sections VI.A.2.,

VI.B.3., supra; see also Ex. 1003, ¶ 123.2. The crosslinked gelatin of Ikada is “a

natural polymer that can undergo in vivo degradation and absorption . . . .” Ex.

1005, 1:57-60. Furthermore, Figures 3 and 7 disclose residual weight of the hydro-

gel as a function of time in vivo, corresponding to degradation times less than 15

days. Id., Figs. 3, 7. Similarly, the type of gelatin hydrogel (such as Gelfoam) dis-

closed in Sakamoto is a “carrier material constituting the hemostatic agent” having

a biodegradable property of “being absorbed into the living tissue so that there is

no necessity of further action such as removal thereof after the initial application to

the affected site.” Ex. 1006, 3:48-50. Accordingly, Ikada in view of Sakamoto ren-

ders Claim 2 obvious.

3. Ikada in View of Sakamoto Renders Claim 3 Obvious Both Ikada and Sakamoto disclose hydrogels that are “at least partially hy-

drated with an aqueous medium comprising an active agent,” as recited in Claim

3. See Sections VI.A.3., VI.B.4.; see also Ex. 1003, ¶ 123.3. Ikada discloses hy-

drogels that are at least partially hydrated. See Section VI.A.1. As explained in de-

tail above (Section VI.A.1., supra) and in the claim chart (Ex. 1003, ¶ 123.1.[e]),

Ikada further teaches the preparation and use of those partially hydrated hydrogels

for delivering basic Fibroblast Growth Factor (bFGF), which is an active agent

used, for example, for the proliferation of cells. Ex. 1005, 1:13-23, 4:60-65, Ex. 1.

Similarly, Sakamoto discloses the preparation of use of hydrogels that are partially

hydrated with Factor XII and thrombin. Ex. 1003, ¶ 123.3. Specifically, Sakamoto

discloses that hydrogels, including gelatin, “can be mixed with Factor XIII and

thrombin for dissolution, and carrier is treated by the resultant solution and, as a

result, Factor XIII and thrombin can be adsorbed physically.” Ex. 1006, 4:40-41;

see also id., Ex.1 (hydrating gelatin powder with thrombin and Factor XII; id., Ta- ble 1 (using the hemostatic agent thrombin in Comparative Examples 3 and 4). Ac- cordingly, Ikada in view of Sakamoto renders Claim 3 obvious.

4. Ikada in View of Sakamoto Renders Claims 4 and 5 Obvious Ikada does not appear to disclose a hydrogel where “the active agent is a clotting agent,” as recited in Claim 4, nor does Ikada appear to disclose “thrombin” as the active agent, as recited in Claim 5. Ex. 1003, ¶¶ 123.4-123.5. As ex-

plained in the context of Sakamoto above, Sakamoto reports that the hydrogels it

discloses, including gelatin, can be mixed with “thrombin for dissolution.” A per-

son of ordinary skill in the art would have known to combine the hydrogels of Ika-

da with the thrombin active agent disclosed in Sakamoto. Id., ¶ 118. Ikada disclos-

es such hydrogels in the context of a drug delivery system, Sakamoto discloses such hydrogels in the context of both a drug delivery system and a hemostat.

Therefore, a person of skill in the art would know to combine the hydrogels with the swelling characteristics disclosed in Ikada and with the active agent (e.g.,

thrombin) disclosed in Sakamoto for purposes of achieving hemostatis. Id., ¶ 118.

Accordingly, Ikada in view of Sakamoto renders Claims 4 and 5 obvious.

5. Ikada in View of Sakamoto Renders Claim 6 Obvious Both Ikada and Sakamoto disclose “a method for delivering an active agent

to a patient,” where the method comprises “administering to a target site on the

patient an amount of the hydrogel” of the type claimed in Claim 3, as recited in

Claim 6. See Sections VI.A.4., VI.B.5., supra; see also Ex. 1003, ¶ 123.6. Ikada

discloses that bFGF-containing crosslinked gelatin gel compositions can be subcu-

taneously implanted into back portions of mice (Ex. 1005, Test Example 1) and cut

portions of rat fibula (id., Test Example 10). In addition, Test Example 9 de-

scribes injecting gelatin gel particles into a rat ilium. Id., 18:65-19:2. Similarly

Sakamoto discloses delivering thrombin and Factor XIII to a bleeding site by fix-

ing the active agents to a carrier hydrogel. Ex. 1006, 4:57-5:3. Example 1 shows

delivery of thrombin and Factor XIII to a female rat by administering to the site of

hepatic biopsy an amount of gelatin hydrogel containing the active agents. See id.,

5:45-6:5. Furthermore, comparative Examples 3-4 in Table 2 of Sakamoto demon-

strate hemostasis with a hemostatic agent containing thrombin. See id., 7:33-34.

Accordingly, Ikada in view of Sakamoto renders Claim 6 obvious.

6. Ikada in View of Sakamoto Renders Claim 7 Obvious Ikada does not appear to disclose a “method for delivering a clotting agent to a patient,” as recited in Claim 7. Ex. 1003, ¶ 123.7. As explained with respect to

Claims 4 and 5 in the context of Ikada in view of Sakamoto above, it would have been obvious to a person of ordinary skill in the art to replace the active agent in

Ikada (bFGF) with the active agent (thrombin) disclosed in Sakamoto. Id., ¶ 118.

Example 1 of Sakamoto describes delivery of thrombin to a female rat. Ex. 1006,

5:45-6:3. Claim 7 also requires that the claimed method comprise “administering from the applicator to a bleeding target site an amount of the hydrogel of claim 4 sufficient to inhibit bleeding.” Ex. 1003, ¶ 123.7. In particular, Example 1 of Sa- kamoto discloses the application of the “gel-formed hemostatic agent” made from

Gelfoam powder through the use of an applicator—in this case a syringe with a biopsy needle—to a biopsy site after which hemostasis (i.e., inhibition of bleeding) was observed. Ex. 1006, 5:58-6:5. Ikada also inherently discloses the use of an applicator, such as a syringe, to deliver hydrogels with an active agent to a patient.

Accordingly, Ikada in view of Sakamoto renders Claim 7 obvious.

7. Ikada in View of Sakamoto Renders Claim 8 Obvious

Ikada does not appear to disclose a “method for delivering thrombin to a

patient,” as recited in Claim 8. Ex. 1003, ¶ 123. However, it would have been ob-

vious to a person of skill in the art to combine the teachings of Ikada with those of

Sakamoto and replace the active agent in Ikada with the active agent in Sakamoto.

Id., ¶ 118. As explained above for Claim 7, Example 1 of Sakamoto describes de-

livery of thrombin to a subject via a hydrogel as a carrier. Ex. 1006, 5:45-6:3.

Claim 7 also requires that the claimed method comprise “administering from the

applicator to a bleeding target site an amount of the hydrogel of claim 5 suffi-

cient to inhibit bleeding. As explained with respect to Claim 7, of Sakamoto dis-

closes the application of the “gel-formed hemostatic agent” made from Gelfoam

powder through the use of an applicator—in this case a syringe with a biopsy nee-

dle—to a biopsy site after which hemostasis (i.e., inhibition of bleeding) was ob-

served. Ex. 1006, 5:58-6:5. Accordingly, Ikada in view of Sakamoto renders

Claim 8 obvious.

VII. SECONDARY CONSIDERATIONS For evidence of commercial success to be pertinent to an evaluation of obvi-

ousness, there must be a nexus between the commercial success and the merits of

the claimed invention. That is, the commercial success must be shown to be due to

the nature of the invention as claimed as opposed to other factors, such as econom- ic and commercial factors, unrelated to the technical quality of the patented inven-

tion. Baxter has contended that its own product, FLOSEAL, is covered by the claims of the ’325 Patent. See Ex. 1024, ¶ 62. Baxter has filed suit against Ethicon in the U.S. International Trade Commission and the U.S. District Court for the

Northern District of Illinois contending that Ethicon’s SURGIFLO product is covered by the claims of the ’325 Patent. See Exs. 1021-1023. As explained by Dr.

Mooney, there is no evidence that any purported success of either FLOSEAL or

SURGIFLO is due to the characteristics set forth in the asserted patent claims as opposed to other factors. See Ex. 1003, ¶ 126. There is no evidence indicating that any success of FLOSEAL or SURGIFLO is due to any merits deriving primarily from the specific features, or combinations of features, recited in the ’325 Patent claims, such as, for example, the claimed equilibrium swell range. Id. In fact, one of Baxter’s own publications (the “Lewis” article) concludes that the surface of

FLOSEAL granules is different from the surface of SURGIFLO granules and further concludes that, because of this difference, FLOSEAL has an increased ability to retain thrombin and red blood cells which may explain what the authors claim is superior hemostatic effectiveness, superior control of bleeding, and greater reduced

blood loss in vivo. Ex. 1013, p. 146-147. Thus, Baxter represents that the surface

configuration of FLOSEAL makes it a superior hemostat to SURGIFLO. But the

’325 Patent claims are not limited to particles having any particular surface config-

uration. Thus any allegedly superior performance of FLOSEAL is not attributable

to any feature claimed by the ’325 Patent. See Ex. 1003, ¶ 127. Furthermore, evidence of any commercial success must be commensurate with the scope of the patent claims. Id., ¶ 128. In this regard, there is no evidence of commercial success that is commensurate with the scope of the ’325 Patent claims. Id.

There is also no evidence that prior to the purported invention of the ’325

Patent there existed a long-felt need for the claimed invention. Id., ¶ 129. As discussed above, prior to the invention of FLOSEAL, Gelfoam powder (a fragmented, resorbable, cross-linked gelatin powder hemostat) had been on the market for years, was known as an effective hemostatic material, and was disclosed as being extrudable and capable of delivery through a syringe. Prior art references such as

Cantor, published in 1950, disclosed that Gelfoam powder, including in combination with thrombin, was a highly effective hemostatic agent that could be delivered from a syringe. Ex. 1008, pp. 891-892. Furthermore, as explained in prior art references such as Sakamoto and Schramm, Gelfoam powder has the attributes covered by the ’325 Patent claims, so any purported problem that may have existed with extruding Gelfoam from a syringe is not a problem that was fulfilled by the invention claimed in the ’325 Patent. There is also no evidence that Gelfoam powder was not as effective as FLOSEAL. And, as explained by Dr. Mooney, it would be surprising if Baxter would contend that Gelfoam powder is not an effective and useful hemostat since it currently sells Gelfoam powder, which it obtains from

Pfizer (the company that acquired Upjohn, the original manufacturer of Gelfoam powder) in its Gelfoam Plus Powder kit. See Ex. 1003, ¶ 130; see also Ex. 1017.

There is also no evidence that Baxter’s FLOSEAL product has received any industry recognition attributable to the features claimed in the ’325 Patent. See i

Ex. 1003, ¶ 131. There is also no evidence that Ethicon, the company that markets

SURGIFLO, tried to copy FLOSEAL. In fact, the Lewis article confirms that the

products are quite different strongly supporting that there was no copying.

Finally, there is no evidence that FLOSEAL has achieved any unexpected

results attributable to the features claimed in the ’325 Patent. As explained in this

petition and in the accompanying expert declaration of Dr. Mooney, FLOSEAL

was not the first flowable hemostat to allow delivery in difficult to reach places.

See id., ¶ 132. Gelfoam powder could be extruded by syringe into such places.

Moreover, the claimed particle size and equilibrium swell ranges were known in

the art and are not attributable to any alleged unexpected, superior properties.

VIII. CONCLUSION The prior art identified in this Petition provide new, non-cumulative techno-

logical teachings which show a reasonable likelihood of success as to Petitioner’s

assertion that the Challenged Claims of the ’325 Patent are not patentable pursuant

to the grounds presented. Petitioner respectfully requests institution of IPR for the

Challenged Claims of the ’325 Patent for each of the grounds presented herein.

Respectfully submitted,

Dated: March 26, 2015 /Dianne B. Elderkin/ Dianne B. Elderkin Reg. No. 28,598 Counsel for Petitioner

CERTIFICATE OF SERVICE Pursuant to 37 C.F.R. § 42.6(e) and 42.105(a), the undersigned certifies that it caused to be served a true and correct copy of the foregoing PETITION FOR

INTER PARTES REVIEW OF U.S. PATENT NO. 6,066,325 (including accompanying exhibits 1001-1024) by Federal Express, on March 26, 2015, on the

Patent Owners at the correspondence address of record for the subject patent:

Kilpatrick Townsend & Stockton LLP Two Embarcadero Center 8th Floor San Francisco, CA 94111-3834

And, the undersigned further certifies that it caused to be served a true and

correct copy of the foregoing PETITION FOR INTER PARTES REVIEW OF

U.S. PATENT NO. 6,066,325 (including accompanying exhibits 1001-1024) by

Federal Express, on March 26, 2015, on the attorneys of record in the concurrent

litigation matter as follows:

Leora Ben-Ami Kirkland & Ellis LLP 601 Lexington Avenue New York, NY 10022

Date: March 26, 2015 /Dianne B. Elderkin/ Dianne B. Elderkin Reg. No. 28,598