`
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`
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`Paper No. ___
`Filed: April 17, 2019
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`MODERNA THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`PROTIVA BIOTHERAPEUTICS, INC.,
`Patent Owner.
`_____________________________
`
`Case IPR2018-00739
`Patent No. 9,364,435
`_____________________________
`
`PATENT OWNER’S REPLY TO
`OPPOSITION TO CONTINGENT MOTION TO AMEND
`
`
`
`TABLE OF CONTENTS
`
`
`
`Page
`
`I.
`
`II.
`
`INTRODUCTION .......................................................................................... 1
`
`THE OPPOSITION DOES NOT ARTICULATE A PRIOR
`ART CHALLENGE ....................................................................................... 1
`
`III. THE PROPOSED AMENDMENTS ARE RESPONSIVE ........................... 2
`
`A.
`
`B.
`
`C.
`
`The Term “Serum Stable” Limits the Scope of the Claims ................. 2
`
`The Amendments are Responsive to the Challenges ........................... 3
`
`Petitioner Asserts a False Narrative of Cationic Lipid
`Toxicity ................................................................................................ 4
`
`D. Nuclease Resistance ............................................................................. 6
`
`IV. THE SUBSTITUTE CLAIMS RECITE CONCENTRATION
`RANGES THAT DISTINGUISH OVER THE PRIOR ART ....................... 7
`
`A. Overlapping Ranges ............................................................................. 7
`
`B.
`
`Unexpected Results Support the Nonobviousness of the
`Claims ................................................................................................... 8
`
`V.
`
`THE PROPOSED SUBSTITUTE CLAIMS ARE
`SUPPORTED AND ENABLED .................................................................... 9
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`The Specification Describes mRNA .................................................... 9
`
`The Specification Enables mRNA ..................................................... 10
`
`Petitioner’s Arguments are Contrary to Its Own
`Publications ........................................................................................ 10
`
`Petitioner’s Arguments are Contrary to Its Own Positions ................ 11
`
`Petitioner’s Secret Testing Further Undermines Its
`Arguments .......................................................................................... 11
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`- i -
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`
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`F.
`
`Petitioner’s Reliance on an Unrelated Proceeding is
`Improper ............................................................................................. 12
`
`VI. CONCLUSION ............................................................................................. 12
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`- ii -
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`
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`I.
`
`INTRODUCTION
`Petitioner’s Opposition to Patent Owner’s Motion to Amend fails on
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`multiple level to demonstrate the unpatentability of the substitute claims.
`
`
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`The Opposition does not even attempt to articulate a challenge over the prior
`
`art, instead referring vaguely to the prior art without identifying any prior art, or
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`explaining how it applies to the substitute claims. Petitioner’s remaining arguments
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`are equally unavailing, and Petitioner falls far short of demonstrating the
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`unpatentability of the claims over the prior art by a preponderance of the evidence.
`
`Petitioner spuriously asserts that the proposed amendments are not described
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`and are not enabled. In making those arguments, Petitioner ignores its own
`
`publications that are directly to the contrary, as well as in direct conflict with
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`positions it has taken in related IPR2018-00680.
`
`II. THE OPPOSITION DOES NOT ARTICULATE A PRIOR ART
`CHALLENGE
`As a threshold matter, the Opposition (e.g., 8, vaguely referencing the “prior
`
`art”) fails to articulate a single prior art challenge, leaving it to Patent Owner to
`
`speculate as to Petitioner’s theory of unpatentability for the substitute claims. To
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`the extent any prior art challenge may be discerned from the nebulous arguments
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`being made in the Opposition, Petitioner does not appear to be advancing an
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`anticipation ground. Moreover, as to obviousness, the Opposition does not identify
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`any specific prior art references being relied upon, any specific theory of
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`- 1 -
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`
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`obviousness, any combination being made, any reason for the combination, or any
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`reasonable expectation of success. Graham v. John Deere Co., 383 U.S. 1, 17
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`(1966).
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`
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`Petitioner cannot meet its burden of proving the obviousness of the
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`substitute claims based on arguments made against different claims in other papers
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`that have apparently been transported into the Opposition. The burden is squarely
`
`on petitioners to prove the unpatentability of the claims. Aqua Products Inc. v.
`
`Matal, 872 F.3d 1290, 1296 (2017) (en banc); see also Scentair Technologies, Inc.
`
`v. Prolitec, Inc., IPR2013-00179, Paper 75, 20 (Apr. 10, 2019); 37 C.F.R.
`
`§42.6(a)(3). This failure alone is fatal to Petitioner’s challenge of the substitute
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`claims.
`
`III. THE PROPOSED AMENDMENTS ARE RESPONSIVE
`A. The Term “Serum Stable” Limits the Scope of the Claims
`Although Patent Owner believes that the addition of “serum stable” is
`
`superfluous under the correct interpretation of nucleic acid-lipid particle (see
`
`Response 11-13), its addition is responsive to the claim construction adopted by
`
`the Board in its Institution Decision (9-10) and the grounds of unpatentability. The
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`addition of “serum stable” to the preamble reinforces that the claims require a
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`particle in which the nucleic acid is encapsulated in the particle so as to protect the
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`nucleic acid from enzymatic degradation. Response 11-13; EX1001, 22:55-62;
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`- 2 -
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`
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`EX2009, ¶¶38-40, 44-45; EX2040, ¶¶23, 39-40. Moreover, “serum stable” is tied
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`to the added limitation of “wherein the particle is formulated such that the nucleic
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`acid is not substantially degraded after exposure of the particle to a nuclease at
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`37ºC for 20 minutes.” The addition of “serum stable” reiterates that the structure of
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`the claimed nucleic acid lipid particles encapsulates the nucleic acid such that the
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`nucleic acid is protected from enzymatic degradation.
`
`B.
`The Amendments are Responsive to the Challenges
`Grounds 1 (Pet. 32) and 2 (Pet. 48) both rely on ʼ196 PCT (EX1002) and the
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`ʼ189 publication (EX1003). Both references specifically state that cationic lipid
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`“may comprise from about 5% to about 15% of the total lipid present in the
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`particle.” EX1002, ¶88; EX1003, ¶152. The proposed amendments relate to serum
`
`stability and nuclease resistance, limiting the claimed particles to those that are
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`suitable for systemic use. The overlapping range argument for the ʼ196 PCT and
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`ʼ189 publication is inapposite when using higher amounts of any cationic lipids in
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`particles for systemic use. Although it is true that “may” can be permissive (Opp.
`
`5), the context of the sentence does not support the notion that a POSITA would
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`read that statement for anything other than what it says, or only applying to certain
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`types of cationic lipids. The Opposition (6) further cites to 2:40 particles disclosed
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`in the ʼ189 publication (EX1003, ¶¶350-391), but those particles are not within the
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`recited cationic lipid concentration range of “50 mol % to 75 mol,” and Petitioner
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`- 3 -
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`
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`does not provide a reason to increase the amount of cationic lipid, especially in
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`view of the teaching that particles for systemic use should have lower (about 5-
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`15%) cationic lipid.
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`The addition of Lin and Ahmad in ground 2 does not help Petitioner, as Lin
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`and Ahmad are drawn to lipoplex formulations that are not described as being
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`suitable for transfection of cells in the presence of serum. (EX1005, 3315; EX1006,
`
`747), failing to provide a reason to modify prior art nucleic acid-lipid particles with
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`any reasonable expectation of success
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` Ground 3 (Pet. 51) relies on the ʼ554 publication, which uses chemically
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`modified RNA constructs to protect the nucleic acid from enzymatic degradation.
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`EX1004, ¶¶522, 523, 578. The proposed amendments distinguish the claimed
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`particles from those of the ʼ554 publication, as the ʼ435 patent defines that serum
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`stability and nuclease resistance are due to the nucleic acid being encapsulated
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`within the lipid portion of the particle. EX1001, 22:55-62.
`
`C.
`Petitioner Asserts a False Narrative of Cationic Lipid Toxicity
`Cationic lipids were known as a group to be toxic at the time of invention,
`
`and thus the conventional thinking was that their content in particle formulations
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`for systemic use should be minimized. The Opposition (5-6) offers, through
`
`attorney argument, a false narrative that ionizable cationic lipids used (e.g.,
`
`DLinDMA) were known as being non-toxic. This argument is remarkable
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`- 4 -
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`
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`considering that Petitioner has published extensively about toxicity concerns due
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`specifically to ionizable cationic lipids, including DLinDMA. EX2051, 21:10-12
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`(noting that ionizable cationic lipids, such as DLinDMA, “have been shown to
`
`accumulate in plasma and tissues over time and may be a potential source of
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`toxicity”); see also EX2052, 57:29-58:9 (“[T]he lipid compounds disclosed herein
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`have a lower immunogenicity as compared to a reference amino lipid (e.g., MC3,
`
`KC2, or DLinDMA).”). Ahmad (EX1006) expressly advocates for multivalent
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`cationic lipids so as to maintain charge with a fewer number of molecules,
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`contradicting the Opposition’s (5) erroneous argument that that toxicity is “largely
`
`a function of such particles having a net positive charge.”
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`Further, Dr. Thompson’s testimony does not support the notion that
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`ionizable cationic lipids, such as DLinDMA, were recognized as non-toxic,
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`testifying only that it “was on the lower end of the toxicity spectrum.” EX1020,
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`268:12-15; see also id. 411:10-12 (“Cationic lipids are toxic. Some are – have
`
`greater toxicity than others, but they’re all toxic.”). Dr. Thompson also directly
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`addressed and rejected the false notion that toxicity is merely a function of surface
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`charge. E.g., EX1020, 244:8-9 (“It doesn't matter whether [the cationic lipid is]
`
`protonatable or not. It’s still toxic.”). Similarly, the Opposition (6-7) incorrectly
`
`asserts that Patent Owner is ignoring the in vivo efficacy of a particle having 52
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`- 5 -
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`
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`mol% DMOBA; that is irrelevant as toxicity was never assessed in the ʼ554
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`publication. E.g., EX1004, ¶408, Table IV, FIG. 29.
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`D. Nuclease Resistance
`The substitute claims further add a limitation to nuclease resistance to the
`
`body of the claim. The Opposition (7) argues that testing for nuclease resistance
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`was commonplace, and that “[e]ach of the three primary references disclose
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`nucleic acid-lipid particles that can also withstand nuclease exposure.” Petitioner
`
`does not explain how the ability to test for nuclease resistance renders obvious the
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`claimed particles. Merely because it may have been commonplace to test for
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`nuclease resistance does not mean that it was commonplace to produce nucleic
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`acid-lipid particles with the claimed lipid components in the claimed
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`concentrations that conferred nuclease resistance. The Opposition (7-8) also only
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`provides a string cite to numerous paragraphs from the ’196 PCT, ’189 publication,
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`and ’554 publication, without explanation, which is insufficient to meet its burden
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`of demonstrating the unpatentability of the substitute claims.
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`
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`The Opposition (8, citing EX1004, ¶578) also erroneously argues that testing
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`done in the ʼ554 publication showed nuclease resistance for systemic
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`administration. As discussed above, the ’554 publication takes a fundamentally
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`different approach in critically relying on chemically modified RNA constructs,
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`indicating particles with significant nuclease exposure. EX1004, ¶¶522, 523, 578.
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`- 6 -
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`
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`Petitioner also offers no explanation as to how “encapsulation” would be
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`understood in the context of the ’554 publication. E.g., EX2028, 137:16-138:16
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`(“[Encapsulation] has many different meanings…”), 147:18-22 (“[Encapsulation
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`is] a fungible term…).
`
`IV. THE SUBSTITUTE CLAIMS RECITE CONCENTRATION RANGES
`THAT DISTINGUISH OVER THE PRIOR ART
`A. Overlapping Ranges
`The Opposition (8) advances the position that the overlap between the prior
`
`art and claimed ranges is now more significant. But Petitioner does not cite to any
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`asserted prior art teaching such overlap, or make any comparison between claimed
`
`and prior art ranges. In fact, the Opposition (8) and Dr. Janoff’s Declaration
`
`(EX1022, ¶62) fail to address any range for the claimed lipid components other
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`than that for the cationic lipid. The burden of persuasion rests on the petitioner to
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`demonstrate the unpatentability of the substitute claims, and Petitioner’s
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`conclusory statement as to overlapping ranges falls far short of meeting this
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`burden.
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`Petitioner also fails to acknowledge that none of duPont, In re Peterson, or
`
`any other overlapping range case stands for the proposition that an overlapping
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`range in the prior art obviates the requirements for motivation to combine and
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`reasonable expectation of success in an obviousness challenge. Instead, the Federal
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`Circuit has explained that overlapping ranges, without evidence to the contrary,
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`- 7 -
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`may invoke a rebuttable presumption of obviousness under the specific rationale of
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`“routine optimization.” Petitioner offers no argument or evidence demonstrating
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`that arriving at the claimed ranges of the lipid components was routine, and in fact
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`the uncontroverted evidence of record is to the contrary.
`
`B. Unexpected Results Support the Nonobviousness of the Claims
`The substitute claims narrow the cationic lipid range to 50% to 75%—a
`
`range coextensive with the data demonstrating unexpected results. E.g., Mot. 16;
`
`see also EX1001, 68:58-64 (lipid ratios as target formulations that may vary by ±5
`
`mol %). The Opposition (9-10, citing EX1022, ¶63) attacks the scope of the data,
`
`asserting that “Patent Owner points to testing of only siRNA payloads with a
`
`limited a limited number of exemplar lipid components and with limited
`
`formulation processes.” Dr. Janoff stated during deposition that he only considered
`
`the data in the ʼ435 patent, undermining his declaratory testimony that the test data
`
`is not commensurate in scope with the claims. E.g., EX2055, 42:10-17. As can be
`
`seen in the Table summarizing the testing data of record (EX2046), many more
`
`than 10 formulations were tested. Moreover, not only siRNA payloads were tested,
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`further undermining Dr. Janoff’s testimony, as it shows he failed to consider all of
`
`the test data of record supporting unexpected and surprising results. Petitioner also
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`does not explain why the experimental data of record, as summarized in Exhibit
`
`2046, is insufficient to support the full scope of the claims.
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`- 8 -
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`
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`V. THE PROPOSED SUBSTITUTE CLAIMS ARE SUPPORTED AND
`ENABLED
`Petitioner (Opp. 10-20) argues that the substitute claims lack written
`
`description support and enablement based on a lack of description and enablement
`
`of a mRNA payload. This argument is surprising in view of Petitioner’s own
`
`publications (which it failed to disclose), as well as the positions it has taken in co-
`
`pending IPR2018-00680.
`
`A. The Specification Describes mRNA
`Petitioner argues that the specification “describ[es] only siRNA” but not
`
`mRNA. Opp. 2, 11. This is flatly wrong. The Motion (6) details written description
`
`support for “nucleic acid,” including mRNA, in the original disclosure and the
`
`earlier-filed specifications, which Petitioner does not specifically refute. E.g.,
`
`EX1001, 10:26-35, claim 2 (reciting mRNA); EX2041, ¶¶10, 19, 25, 26; EX2045,
`
`¶¶17-18, 61, 76, 140, 307; EX2040, ¶28. These disclosures “reasonably convey[]
`
`to those skilled artisan that the inventor had possession of the claimed subject
`
`matter as of the filing date.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336,
`
`1351 (Fed. Cir. 2010). Petitioner (Opp. 14) also asserts that the specification does
`
`not provide any examples of experiments involving nucleic acid-lipid particles
`
`with mRNA payloads. That argument is legally misplaced as experimental
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`examples are not required for written description support. Ariad, 598 F.3d at 1352.
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`- 9 -
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`
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`B.
`The Specification Enables mRNA
`Petitioner’s arguments (Opp. 18) as to enablement are equally unavailing.
`
`The skilled artisan would understand that “once a delivery technology is found
`
`suitable for knocking down genes in a given cell/tissue type, any gene can be
`
`targeted in that cell/tissue type with the possible applications only limited by our
`
`exploding understanding of disease genetics.” EX2015, 4; see also EX1020,
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`405:14-406:7 (Dr. Thompson testifying he would use ʼ435 composition and
`
`methods as first choice for other payloads). And Petitioner is well aware Patent
`
`Owner has been using its formulations for mRNA delivery for years. EX1026,
`
`36:14-37:7. Critically, “[e]nablement is not precluded by the necessity for some
`
`experimentation … The key word is ‘undue’, not ‘experimentation.’” In re Wands,
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`858 F.2d 731, 736-37 (Fed. Cir. 1988).
`
`C.
`Petitioner’s Arguments are Contrary to Its Own Publications
`Petitioner’s own publications contradict its argument (Opp. 15) that “siRNA
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`lipid nucleic acid particles … are poor predictors of mRNA LNP percentages for
`
`optimization,” and demonstrate that any experimentation would not be undue.
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`Sedic explains that an off-the-shelf nucleic acid-lipid particle formulation
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`developed for siRNA (i.e., patisiran) can be used for an 850-nucleotide mRNA, no
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`adjustments needed. EX2048, 2-3; EX2019, ¶13. Using an off-the-shelf
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`formulation is far from “extensive testing” or “undue experimentation.”
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`- 10 -
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`
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`D.
`Petitioner’s Arguments are Contrary to Its Own Positions
`Petitioner has already taken the position that mRNA is described and
`
`enabled by the disclosure of the ʼ435 patent. Specifically, Petitioner argues that the
`
`same disclosure in the ʼ069 patent, of which the ʼ435 patent is a continuation,
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`anticipates the particles of the ʼ127 patent. IPR2018-00680, Paper 26, 19. The
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`Response (Paper 22, 39-40) to the ʼ127 Petition is not to the contrary, as the theory
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`set forth in the ʼ127 Petition (e.g., 25, 33) was one of inherency, i.e., that the ʼ127
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`particles were made using the same formulation, same siRNA payload, and same
`
`formulation process as the particles exemplified in the ʼ069 patent. Petitioner
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`should not be permitted to argue here that a mRNA payload is not enabled by the
`
`disclosure, but to argue that the same disclosure anticipates, and thus necessarily
`
`enables, particles having a mRNA payload in IPR2018-00680. E.g., Advanced
`
`Display Sys., Inc. v. Kent State Univ., 212 F.3d 1272, 1282, (Fed. Cir. 2000).
`
`E.
`Petitioner’s Secret Testing Further Undermines Its Arguments
`At deposition, Dr. Janoff revealed that Petitioner commissioned testing of
`
`mRNA payloads based on the disclosure of the ʼ435 patent. EX2055, 16:12-18:22.
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`That testing was not disclosed by Petitioner in its Reply or Opposition. Although
`
`Dr. Janoff testified Petitioner spent approximately $100,000 and four months
`
`attempting some protocols described in the ʼ435 patent, Dr. Janoff described the
`
`results as not useful and unreliable. Dr. Janoff but not testify as to protocols or
`
`results. Id., 17:3-10, 18:6-19.
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`- 11 -
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`
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`Dr. Janoff’s spin about the purported testing is again directly contradicted by
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`Petitioner’s own published testing, as evidenced by Sedic, which successfully used
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`an off-the-shelf lipid siRNA formulation covered by the amended claims to deliver
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`mRNA. EX2048, 3. Further undermining Petitioner’s credibility, Dr. Janoff
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`testified that he was unfamiliar with the Sedic publication. EX2055, 70:18-71:13.
`
`F.
`Petitioner’s Reliance on an Unrelated Proceeding is Improper
`Incredibly, Petitioner (Opp. 16) cites Ex parte Guild—an appeal involving
`
`an unrelated patent, involving different records, in which neither Petitioner nor
`
`Patent Owner was a party, to support its argument that the ʼ435 patent does not
`
`support mRNA payloads. EX1025. Petitioner’s arguments regarding Guild are
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`entirely irrelevant to the instant proceeding and should not be entertained.
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`VI. CONCLUSION
`The arguments advanced by Petitioner fail to demonstrate that the proposed
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`substitute claims are unpatentable. If an original claim(s) is found unpatentable, the
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`Board should permit entry of its corresponding claim from substitute claims 21-40
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`and allow the claim(s) to issue in the ’435 patent on a claim-by-claim basis.
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`
`
`
`
`Date: April 17, 2019
`
`
`
`Respectfully submitted,
`
`
`/ Michael T. Rosato /
`Michael T. Rosato, Lead Counsel
`Reg. No. 52,182
`
`
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`- 12 -
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`
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`CERTIFICATE OF SERVICE
`
`
`
`This is to certify that I caused to be served a true and correct copy of the
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`foregoing Patent Owner’s Reply to Opposition to Contingent Motion to Amend, on
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`this 17th day of April, 2019, on the Petitioner at the correspondence address of the
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`Petitioner as follows:
`
`Michael Fleming
`C. Maclain Wells
`IRELL & MANELLA LLP
`mfleming@irell.com
`mwells@irell.com
`ModernaIPR@irell.com
`
`
`
`
`
`Date: April 17, 2019
`
`
`
`
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`Respectfully submitted,
`
`
`/ Michael T. Rosato /
`Michael T. Rosato, Lead Counsel
`Reg. No. 52,182
`
`
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`- 13 -
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