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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN INSTITUTIONAL LLC and PFIZER INC.,
`Petitioners,
`v.
`NOVO NORDISK A/S,
`Patent Owner.
`
`Case No. IPR2020-003241
`U.S. Patent No. 8,114,833
`
`REPLY DECLARATION OF LAIRD FORREST, PH.D. IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 8,114,833
`
`REDACTED VERSION
`
`1 IPR2020-01252 has been joined with this proceeding.
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`TABLE OF CONTENTS
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`I. LEGAL STANDARDS ...................................................................................... 5
`II. PERSON OF ORDINARY SKILL IN THE ART.......................................... 6
`III. MATERIALS REVIEWED .............................................................................. 7
`IV. CLAIMS 1-15 OF THE ’833 PATENT WERE ANTICIPATED BY OR
`WOULD HAVE BEEN OBVIOUS OVER FLINK ....................................... 7
`A. Flink Anticipated Claims 1-15 of the ’833 Patent ........................................ 7
`(a) Disclosure of Propylene Glycol ................................................................. 8
`
`(b) Disclosure of Propylene Glycol Concentration Ranges ...........................10
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`(c) Disclosure of Disodium Phosphate Dihydrate Buffer ..............................12
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`(d) Enablement ...............................................................................................16
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`B. Claims 1-15 of the ’833 Patent Would Have Been Obvious In View of
`Flink Alone ..................................................................................................19
`(a) Selection of Propylene Glycol is Obvious ...............................................19
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`(b) Alleged Concerns Regarding Use of Propylene Glycol ...........................26
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`(c) Calculation of Propylene Glycol Concentration Is Obvious ....................36
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`(d) Selection of Disodium Phosphate Dihydrate Buffer is Obvious ..............39
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`(e) Alleged Concerns Regarding Stability of GLP-1 agonists ......................40
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`V. CLAIMS 1-31 OF THE ’833 PATENT ARE OBVIOUS IN VIEW OF
`FLINK AND BETZ .........................................................................................49
`A. The Tessier Declaration confirms the motivation to combine Flink with
`Betz..............................................................................................................49
`B. A POSA would find Betz highly relevant to GLP-1 agonist formulations 52
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`TABLE OF CONTENTS
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`pH of Betz formulations is not relevant propylene glycol’s function .........65
`C.
`D. Teachings of Betz ........................................................................................68
`VI. THERE WERE NO UNEXPECTED RESULTS .........................................72
`VII. BETZ IS PRIOR ART TO THE ’833 PATENT ....................................80
`A. Betz is Entitled to a Priority Date of July 9, 2002 ......................................80
`B.
`Patent Owner Has Not Established an Actual Reduction to Practice .........87
`(a) Exhibit 2053 .............................................................................................91
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`(b) Exhibit 2055 .............................................................................................92
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`(c) Exhibit 2057 .............................................................................................92
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`(d) Exhibit 2058 .............................................................................................93
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`(e) Exhibit 2059 .............................................................................................94
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`(f) Exhibit 2064 .............................................................................................95
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`(g) Exhibit 2068 .............................................................................................96
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`(h) Exhibit 2072 .............................................................................................96
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`(i) Exhibit 2069 .............................................................................................97
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`(j) Exhibit 2052 .............................................................................................99
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`(k) Remaining documents ............................................................................112
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`(l) Claims 26-28...........................................................................................113
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`1.
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`I, Laird Forrest, Ph.D., have been retained by Mylan Institutional LLC
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`(“Mylan”) in the matter set forth in the caption above. I submitted previously an
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`expert declaration in this matter, dated December 19, 2019, which was designated
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`Exhibit 1002 (“First Declaration”). In that declaration, I showed that claims 1-31 of
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`U.S. Patent No. 8,114,833 to Pedersen et al. (“the ’833 patent”) (Ex. 1001) were
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`either anticipated by the prior art or would have been obvious to a person of ordinary
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`skill in the art at their priority date. See generally Ex. 1002.
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`2. My qualifications, previous testimony, and compensation are provided
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`in my Opening Declaration. An updated curriculum vitae is attached hereto as
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`Exhibit A.
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`3.
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`I submit this reply expert declaration in further support of my opinions
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`regarding the ’833 patent, and in reply to certain opinions set forth in the September
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`18, 2020 Declaration of Peter M. Tessier, Ph.D. (“Tessier Declaration”), filed on
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`behalf of the Patent Owners, which was designated Exhibit 2022. To the extent I do
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`not expressly address a point made by Dr. Tessier, it does not mean that I agree with
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`it.
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`4.
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`The scope of my work and compensation remains the same since I
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`submitted my original declarations in this proceeding. I was retained as a technical
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`expert to provide opinions related to the patent at issue. My compensation is not
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`dependent upon the outcome of the proceedings or my opinions given. I have no
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`current affiliation with Novo Nordisk A/S or the inventors of the patent at issue.
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`I.
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`LEGAL STANDARDS
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`5.
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`In addition to the legal principles detailed in my previous declaration, I
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`have been informed by counsel regarding relevant legal principles.
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`6.
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`Counsel has informed me that an international patent application filed
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`on or after November 29, 2000 but prior to March 16, 2013, that designates the
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`United States, and is published in English under the Patent Cooperation Treaty
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`(PCT) is usable for prior art purposes as of its international filing date. If the
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`international patent application claims priority to one or more U.S. provisional
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`application, the international patent application is usable for prior art purposes as of
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`filing date of the earlier filed provisional application provided at least one claim of
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`the international application is supported by the description of the provisional
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`application.
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`7.
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`Counsel has also informed me that a patent owner can submit evidence
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`that it invented the claimed invention prior to the earliest date that a reference is
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`usable for prior art purposes (i.e., the earliest priority date). I understand that one
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`way to show prior invention is to demonstrate an actual reduction to practice prior
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`to the earliest priority date. To do so, I understand that Patent Owner must not only
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`show that they had prepared a formulation that meets every limitation of the claimed
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`invention, but also must show that they had determined that the invention would
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`work for its intended purpose.
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`8.
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`Counsel informed me that a reference is enabling for the purposes of
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`anticipation if it teaches one skilled in the art to make the claimed invention without
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`undue experimentation.
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`9.
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`Counsel also informed me that where a motivation to combine is
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`required, that motivation need not be based on the same problem confronted by the
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`inventors.
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`10. Counsel also informed me that when a party asserts that unexpected
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`results should preclude a finding of obviousness, the party asserting unexpected
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`results must compare the closest prior art to the claims at issue and demonstrate that
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`the results were unexpected, and that results that differ only as to degree do not rise
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`to the level of unexpected results. I also understand that the allegedly unexpected
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`results must be unexpected across the entire scope of the claim, and that when a
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`range is claimed, the results must be unexpected across the entire claimed range.
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`II.
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`PERSON OF ORDINARY SKILL IN THE ART
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`11.
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`I continue to apply the definition of the person of ordinary skill in the
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`art (“POSA”) described in my First Declaration (Ex. 1002): a (1) a Pharm. D., or a
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`Ph.D. in pharmacy, chemical engineering, bioengineering, chemistry, or related
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`discipline; with (2) at least two years of experience in the area of protein or peptide
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`therapeutic development and/or manufacturing; and (3) experience with the
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`development, design, manufacture, or formulation of therapeutic agents, and the
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`literature concerning protein or peptide formulation and design. I understand that the
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`Board adopted this definition of a POSA in its Institution Decision.
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`12.
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`I also understand that Patent Owner’s expert, Dr. Tessier, applied a
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`different definition for POSA in forming his opinions. Ex. 2022 at ¶43. My opinions
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`would not be different if I applied Patent Owner and Dr. Tessier’s definition.
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`III. MATERIALS REVIEWED
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`13.
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`In addition to my experience, education, and training, and the materials
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`identified in my opening declaration (Ex. 1002), I have also considered all materials
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`identified in Exhibit B, as well as any materials cited herein not otherwise identified
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`in Exhibit B.
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`IV. CLAIMS 1-15 OF THE ’833 PATENT WERE ANTICIPATED BY OR
`WOULD HAVE BEEN OBVIOUS OVER FLINK
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`A. Flink Anticipated Claims 1-15 of the ’833 Patent
`14. As stated in my First Declaration, it remains my opinion that claims 1-
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`15 of the ’833 patent were anticipated by Flink, notwithstanding Dr. Tessier’s
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`assertions to the contrary. I respond to certain of Dr. Tessier’s assertions below.
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`15. As an initial matter, I note that my opinion that Flink anticipates claims
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`1-10 of the ’833 patent was and remains based primarily on claim 14 of Flink. As I
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`explained in my First Declaration, I understand claim 14 to be a dependent claim
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`that requires all elements of the claims from which it depends. In particular, my
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`opinion regarding claim 14 is based on the embodiment described through its
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`dependence on claims 13, 12, 11, 10, 8, 6, and 5. I also note that my opinion that
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`Flink anticipates claims 11-15 of the ’833 patent was and remains based primarily
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`on claims 21-25 of Flink, based on the embodiments described through their
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`dependencies as identified in my First Declaration. See Ex. 1002 at ¶¶178-187. A
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`POSA would understand that the claims are part of Flink’s disclosure and comprise
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`embodiments of the invention. I also understand that the claims are read in light of
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`Flink’s disclosure. During his deposition, Dr. Tessier admitted that a POSA would
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`evaluate the entire patent to determine how the patent defines certain claim terms to
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`determine the scope of what those terms encompass, even though he did not follow
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`his own advice, as discussed below. See. Ex. 1077 at 17:18-18:14.
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`(a) Disclosure of Propylene Glycol
`16. Dr. Tessier states that Flink “discloses broad categories of chemicals,
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`each of which is a genus that includes a large number of possibilities, that could
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`hypothetically be useful as isotonicity agents,” and that “[e]ach genus is presented
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`with one or more examples of a chemical falling within that genus, identified by
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`‘e.g.’” Ex. 2022 at ¶133. Dr. Tessier also states that propylene glycol is identified as
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`an example of an isotonic agent that falls within the polyhydric alcohol genus
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`disclosed by Flink. Id. However, Dr. Tessier’s assertions that “Flink puts no
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`emphasis on propylene glycol and a person of ordinary skill in the art reading the
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`reference would not envision a formulation containing it, as opposed to any of the
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`other possible isotonicity agent options” among the six genuses disclosed, and that
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`“Flink’s disclosure of genuses, with identified examples thereof, would not have
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`been understood by a person of ordinary skill in the art as a teaching that every
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`chemical identified as an example could be used with GLP-1 as an isotonicity agent”
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`are simply not true in my opinion from the perspective of one skilled in the art. Ex.
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`2022 at ¶¶133, 141.
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`17. As Dr. Tessier acknowledges, Flink’s disclosure does in fact identify
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`eighteen exemplary species of isotonic agents, including propylene glycol, from the
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`“hundreds of different chemicals [that] could have been used as possible isotonicity
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`agents.” Ex. 2022 at ¶¶133, 140; Ex. 1004 at 19-20. Contrary to Dr. Tessier’s
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`assertion (and against his own acknowledgement during his deposition, see Ex. 1077
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`at 17:18-18:14), one skilled in the art would have looked to those exemplary isotonic
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`agents first as preferred or otherwise desirable options from the otherwise long list
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`of agents encompassed by the disclosed genuses. Consequently, one skilled in the
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`art would have at once envisioned propylene glycol as “an isotonic agent” within the
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`meaning of claims 13 and 14 of Flink. Dr. Tessier, on the other hand, admitted that
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`he did not even consider the full scope of claim 14 in forming his opinion, looking
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`only to the examples for guidance. Ex. 1077 at 84:8-86:1.
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`18. Further, Dr. Tessier states that “[p]ropylene glycol was not known in
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`the prior art for its use as an isotonicity agent,” and that a POSA “would have been
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`cautious of using propylene glycol” out of concerns related to instability and side
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`effects, such as hemolysis, pain, thrombophlebitis, and dermatitis. Ex. 2022 at ¶132
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`(citing ¶¶59-64, 68-80). However, the claims do not include any limitations that
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`would require propylene glycol to be used for any particular function, nor do they
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`require the claimed formulation to be free from any side effects. And as I explain in
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`detail below, a POSA would not have excluded propylene glycol based on Dr.
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`Tessier’s concerns. See infra, at ¶¶33-53, 60-72.
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`(b) Disclosure of Propylene Glycol Concentration Ranges
`19. Dr. Tessier also asserts that “[n]owhere does Flink disclose [the range
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`of 1 to 50 mg/ml] of propylene glycol” and suggests that I agreed with him during
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`my deposition. Ex. 2022 at ¶¶142, 161, 162.
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`20. First, I’d like to point out that Dr. Tessier mischaracterizes my
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`testimony. When asked whether Flink disclosed “a particular concentration for
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`propylene glycol,” I answered that “it’s not necessary to give the exact
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`concentration” for several reasons. Ex. 2079 at 119:20-120:19 (emphasis added). I
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`did not agree that Flink fails to disclose the claimed range of concentrations for an
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`isotonic agent such as propylene glycol.
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`21. Further, I disagree with Dr. Tessier’s assertion that Flink does not
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`disclose the claimed concentration ranges. Claims 1-15 of the ’833 patent do not
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`require a particular or exact concentration of propylene glycol. What is claimed is a
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`range of concentrations “from about 1 mg/ml to about 100 mg/ml” (claim 1), “from
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`about 1 mg/ml to about 50 mg/ml” (claim 2), “from about 5 mg/ml to about 25
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`mg/ml” (claim 3), and “from about 8 mg/ml to about 16 mg/ml” (claim 4). Flink
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`expressly discloses the ranges recited in claims 2 and 4 or discloses ranges that
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`wholly encompass the ranges recited in claims 1 and 3. Ex. 1004 at 20:10-16, claim
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`14. A POSA would understand that those ranges would apply to any isotonic agent,
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`including propylene glycol because claim 14 of Flink requires the isotonic agent,
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`i.e., propylene glycol, to be present at a concentration from 1 mg/ml to 50 mg/ml,
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`falling squarely within the recited ranges of claims 1 and 2, and encompassing the
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`ranges recited in claims 3 and 4. Flink’s disclosure also clearly discloses an
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`embodiment in which the isotonic agent, i.e., propylene glycol, is “present in a
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`concentration from 8 mg/ml to 16 mg/ml” (Ex. 1004 at 20:12-13), falling squarely
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`within the recited ranges of claims 3 and 4.
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`22. For at least the reasons I discuss above, Dr. Tessier’s argument that
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`“[t]he single mention of propylene glycol in the specification of Flink, as an example
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`of one of six possible genuses presenting options for possible isotonicity agents, is
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`not a disclosure of a GLP-1 agonist pharmaceutical formulation containing 1 mg/ml
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`to 100 mg/ml of propylene glycol” is untenable. Ex. 2022 at ¶142.
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`23. Dr. Tessier also asserts that “[a] person of ordinary skill in the art would
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`have had to conduct a thorough experimental analysis to determine the appropriate
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`amount of propylene glycol to use to attempt to achieve isotonicity in the
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`formulations under investigation.” Ex. 2022 at ¶144. I disagree because there is no
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`need to calculate a particular concentration of propylene glycol for Flink to
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`anticipate claims 1-15 of the ’833 patent because Flink expressly discloses the
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`claimed ranges as I have discussed above. Indeed, no degree of tonicity is required
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`by the claims.
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`(c) Disclosure of Disodium Phosphate Dihydrate Buffer
`24. Regarding the claimed “disodium phosphate dihydrate buffer,” Dr.
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`Tessier states that the specification discloses an embodiment of the invention
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`wherein “the buffer is selected from the group consisting of sodium acetate, sodium
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`carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium
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`dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and
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`tris(hydroxymethyl)-aminomethan, or mixtures thereof.” Ex. 2022 at ¶147 (quoting
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`Ex. 1004 at 18:27-30). But I take issue with Dr. Tessier’s argument that “disodium
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`phosphate dihydrate” is somehow “not included in the list of buffers in the
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`specification” or “identified as a buffer in a preferred embodiment” despite its
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`express disclosure in Example 7. Ex. 2022 at ¶148 (citing Ex. 1004 at 18:27-33).
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`25. As I explained in my First Declaration, one skilled in the art would have
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`understood that a “buffer” is a solution that resists change in pH. To prepare a buffer,
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`a buffering agent is dissolved in water. In the case of a “disodium hydrogen
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`phosphate” buffer—which is expressly disclosed on page 18 of Flink as a preferred
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`buffer—one skilled in the art would understand that any hydration state of disodium
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`hydrogen phosphate could be used as the buffering agent.2 But, once dissolved, the
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`hydration state of the disodium hydrogen phosphate is necessarily ambiguous,
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`because any hydrate (i.e. water molecules of hydration that are bound to the solid
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`form) would dissociate from the disodium hydrogen phosphate to become part of the
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`aqueous solution. Furthermore, the two sodium cations (i.e., disodium) disassociate
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`from the hydrogen phosphate anion, leaving the hydrogen phosphate anion (HPO4
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`2)
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`in solution as the buffering agent. Regardless of the initial hydrate species used, the
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`identical buffering product will result from the dissolving process inherent to
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`forming an aqueous buffer solution. Ex. 1119 at 3-4. The resulting buffer would be
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`2
`I note that Dr. Tessier acknowledges that a “disodium hydrogen phosphate”
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`buffer is equivalent in nomenclature to a “disodium phosphate” buffer, therefore I
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`only address the hydration state here. Ex. 1077 at 76:21-77:13.
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`referred to by one skilled in the art simply as a disodium hydrogen phosphate buffer.
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`Thus, as I previously stated in my First Declaration, a “disodium hydrogen
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`phosphate” buffer is of the same species as a “disodium phosphate dihydrate” buffer,
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`but the hydration state of disodium hydrogen phosphate is ambiguous because the
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`buffering agent is part of the fully dissolved (i.e., hydrated) aqueous solution, no
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`matter its initial hydrated state. I note that during his deposition, Dr. Tessier stated
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`that he would look at the term “disodium hydrogen phosphate” on page 17
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`(corresponding to page 18 of Exhibit 1004) of Flink to mean that “if there is not a
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`hydrate information listed, that it’s the anhydrous form.” Ex. 1077 at 80:3-15. That
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`is not how a POSA would understand that term for the reasons I’ve stated above.
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`26. Moreover, because Example 7 of Flink discloses disodium phosphate
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`dihydrate as the specific buffering agent used to the prepare disodium hydrogen
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`phosphate buffer, one skilled in the art would have immediately understood that
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`disodium phosphate dihydrate was the specific buffering agent used to prepare the
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`disodium hydrogen phosphate buffer disclosed as a preferred embodiment on page
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`18 of Flink. This understanding applies to the disclosure of the ’833 patent itself.
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`The Detailed Description section of the ’833 patent specification discloses a list of
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`buffers identical to the list disclosed in Flink, as shown side-by-side in the table
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`below:
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`em . hasis added
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`“[T]he buffer is selected from the
`group consisting of sodium acetate,
`sodium carbonate, citrate,
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`glycylglycine, histidine, glycine,
`lysine, arginin, sodium dihydrogen
`phosphate, disodium hydrogen
`ghosghate, sodium phosphate, and
`tris(hydroxymethyl)—aminomethan, or
`mixtures thereof. Each one of these
`
`specific buffers constitutes an
`alternative embodiment of the
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`invention. In a preferred embodiment
`of the invention the buffer is
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`glycylglycine, sodium dihydrogen
`phosphate, disodium hydrogen
`Qhosghate, sodium phosphate or
`mixtures thereof.”
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`
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`
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`em . hasis added
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`“[T]he buffer is selected from the
`group consisting of sodium acetate,
`sodium carbonate, citrate,
`
`glycylglycine, histidine, glycine,
`lysine, arginin, sodium dihydrogen
`phosphate, disodium hydrogen
`ghosghate, sodium phosphate, and
`tris(hydroxymethyl)-aminomethan, or
`mixtures thereof. Each one of these
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`specific buffers constitutes an
`alternative embodiment of the
`
`invention. In a preferred embodiment
`of the invention the buffer is
`
`glycylglycine, sodium dihydrogen
`phosphate, disodium hydrogen
`Qhosghate, sodium phosphate or
`mixtures thereof.”
`
`
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`27.
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`It is only the Examples of the ’833 patent that indicate which hydrated
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`form of the buffering agent is used to prepare the disodium hydrogen phosphate
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`buffer. Thus, the scope of the term “buffer” recited in claim 14 of Flink would
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`encompass a “disodium phosphate dihydrate” buffer just as the same would be
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`supported by the ’833 patent specification. Further, although Example 7 does not
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`include propylene glycol, that does not preclude a finding of anticipation. Claim 14
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`of Flink broadly claims formulations of GLP-1 with various isotonicity agents and
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`buffers and is not limited to specific examples. Example 7 simply includes
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`exemplary embodiments of some of the formulations encompassed by claim 14-
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`28. For the reasons set forth above, it remains my opinion that Flink
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`discloses the claimed disodium phosphate dihydrate buffer and that a POSA would
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`have at once envisioned that the buffer of Flink’s claim 14 (by virtue of its
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`dependence on claim 5) encompasses the same. In sum, Flink anticipated claims 1-
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`15 of the ’833 patent.
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`(d) Enablement
`I understand that a reference is enabling if it teaches one skilled in the
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`29.
`
`art to make the claimed invention without undue experimentation. Claims 1-15 are
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`directed to pharmaceutical formulations having a pH of about 7.0-10.0, that include
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`a GLP-1 agonist, a disodium phosphate dihydrate buffer, and propylene glycol in a
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`range of claimed concentrations—all within the range of about 1 mg/ml to about 100
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`mg/ml. As discussed above (see supra at ¶¶15-28) and in my First Declaration, Flink
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`expressly disclosed all the limitations of the claimed formulations. As such, it would
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`not require a POSA to perform any experiments to make the claimed formulation as
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`it would simply require combining the claimed ingredients. Preparing the
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`formulation may also require one skilled in the art to prepare the buffer and adjust
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`the pH to the claimed level, but that is well within the skill of a POSA. Dr. Tessier
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`does not dispute that. Indeed, the ’833 patent itself concedes that techniques to
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`manufacture the claimed formulations are routine. Ex. 1001 at 12:64-13:29 (“The
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`formulations of the invention may be prepared by conventional techniques, e.g., as
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`described in Remington’s Pharmaceutical Sciences, 1985 or in Remington: The
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`Science and Practice of Pharmacy, 19th edition, 1995, where such conventional
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`techniques of the pharmaceutical industry involve dissolving and mixing the
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`ingredients as appropriate to give the desired end product.”). In fact, Flink describes
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`in the Examples that “[t]he pH was adjusted to the specified using Sodium
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`Hydroxide and/or Hydrochloric Acid.” Ex. 1004 at 38:14-15, 39:5-6, 40:4-5, 41:4-
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`5, 42:9-10, 44:3-4.
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`30. Dr. Tessier does, however, assert that a POSA would have “needed to
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`conduct a series of experiments to determine whether a pharmaceutical formulation
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`of GLP-1 and propylene glycol would have worked for its intended purpose.” Ex.
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`2022 at ¶158. Specifically, Dr. Tessier states that a POSA would have needed to
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`“test the compatibility of propylene glycol with the other excipients; identify through
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`experimentation an amount of propylene glycol that would render the formulation
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`isotonic; ensure the formulation was safe, tolerable, and did not come with risk of
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`microbial contamination; confirm that propylene glycol did not destabilize GLP-1;
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`and devise a suitable method for making the formulation.” Ex. 2022 at ¶158.
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`However, I note that all of the tests Patent Owner suggests are necessarily related to
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`functional requirements (e.g., that the formulation is compatible, isotonic, safe,
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`tolerable, not contaminable, stable, etc.). But none of those requirements are recited
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`in the claims, as Dr. Tessier confirmed during his deposition. Ex. 1077 at 15:18-
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`29:7. As such, the claims do not require any action beyond combining the ingredients
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`as recited, as Dr. Tessier concedes. Further, I understand that a reference does not
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`need to demonstrate a use or proof of efficacy to anticipate a claim, and evidence as
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`to whether particular compounds work for their intended purpose is irrelevant to
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`anticipation. Thus, I disagree with Dr. Tessier’s assertion that such testing would be
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`required for Flink to be an enabling disclosure for the purpose of anticipation.
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`31. Further, the tests listed by Dr. Tessier would only have been used to
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`confirm what a POSA would have already expected: that propylene glycol was
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`known to be compatible with phosphate buffers—including those prepared with
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`disodium phosphate (Ex. 1120 at Abstract, 3); that calculating the amount of
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`propylene glycol to use would result in a sufficiently isotonic solution for the
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`purposes of a drug formulation delivered via injection or any other in vivo
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`administration (see infra at ¶¶35-36, 39-57); that no additional toxicity studies were
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`needed (see infra at ¶38); that propylene glycol was known to have antimicrobial
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`properties similar to ethanol (see, e.g., Ex. 1022 at 17; Ex. 1023 at 17); that propylene
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`glycol would not have been expected to destabilize GLP-1 (see infra at ¶¶60-72);
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`and that the formulation could be prepared, tested, and evaluated using any suitable
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`method known in the art (Ex. 1001 at 12:64-13:29; Ex. 1002 at ¶¶209, 214-217; Ex.
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`1004 at 38:13-16, 41:3-6, 42:7-11; 44:2-5; Ex. 1005 at 15-17; see also Exs. 1125-
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`1126). Even if the tests identified by Dr. Tessier were to be required, they are all
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`standard tests used to confirm the functionality of a protein formulation, regardless
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`of the protein or peptide.
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`. These and other standard tests were well-known, within the ability
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`of the POSA, and would not amount to undue experimentation. Procedures to
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`conduct standard tests are described in numerous treaties and regulatory standards
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`familiar to the POSA, including Remington’s Pharmaceutical Sciences, 18th edition,
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`1990. See Ex. 1013 (“Remington 1990”); see also Ex. 2081 (“Remington 1995”);
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`Ex. 1068 (U.S. Pharmacopeia (USP-NF)).
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`B. Claims 1-15 of the ’833 Patent Would Have Been Obvious In View
`of Flink Alone
`It also remains my opinion that claims 1-15 of the ’833 patent would
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`32.
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`have been obvious over Flink alone. I respond to certain of Dr. Tessier’s assertions
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`below.
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`Selection of Propylene Glycol is Obvious
`(a)
`33. Regarding whether it would have been obvious to one skilled in the art
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`to have selected propylene glycol as an isotonic agent in view of claim 14 and the
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`rest of Flink’s disclosure, Dr. Tessier again asserts that he would not consider Flink’s
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`disclosure of eighteen exemplary isotonic agents to be a “‘short list,’ but rather an
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`expansive set of categories of chemicals that could be considered for adjusting
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`tonicity, followed by the disclosure of nine alternative actual isotonicity agents and
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`mixtures thereof, none of which is propylene glycol followed by two preferred
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`options, neither of which is propylene glycol.” Ex. 2022 at ¶181. In fact, as discussed
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`above, I understand that Dr. Tessier did not even consider the full scope of claim 14
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`for his analysis. Ex. 1077 at 84:8-86:1. Thus, for the same reasons discussed above
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`in ¶¶14-28, I disagree. Also, contrary to Dr. Tessier’s opinions, it is my
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`understanding that “preferred” options or embodiments are irrelevant to whether
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`claims 1-15 are obvious in view of Flink and that all disclosures of a prior art
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`reference must be considered, including embodiments that are less preferred. Ex.
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`2022 at ¶¶181, 186.
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`34. Dr. Tessier also asserts that Flink “indicated that inclusion of an
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`isotonicity agent was optional” and thus would not have taught a POSA propylene
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`glycol. Ex. 2022 at ¶180. First, I note that inclusion of an isotonicity agent is required
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`by claim 14 and is therefore not “optional” in that embodiment. Additionally, it is
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`my understanding that a component that is “optional” can still render a claim
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`obvious, especially when the disclosure includes embodiment(s) that include that
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`optional component.
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`35.
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`I also note that Dr. Tessier mischaracterizes my opinion rega