UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`Moderna Therapeutics, Inc.
`
`Petitioner
`
`v.
`
`Protiva Biotherapeutics, Inc.
`
`Patent Owner
`___________
`
`Case No. IPR2018-00739
`U.S. Patent No. 9,364,435
`
`_________
`
`DECLARATION OF ANDREW S. JANOFF, PH.D.
`IN SUPPORT OF MODERNA THERAPEUTICS, INC.’S
`PETITIONER’S OPPOSITION TO PATENT OWNER’S
`CONTINGENT MOTION TO AMEND
`
`Mail Stop: PATENT BOARD
`Patent Trial and Appeal Board
`U.S. Patent & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`10656042
`
`
`
`Moderna Ex 1022-p. 1
`Moderna v Protiva
`IPR2018-00739
`
`
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`Moderna Therapeutics, Inc.
`
`Petitioner
`
`v.
`
`Protiva Biotherapeutics, Inc.
`
`Patent Owner
`___________
`
`Case No. IPR2018-00739
`U.S. Patent No. 9,364,435
`
`_________
`
`DECLARATION OF ANDREW S. JANOFF, PH.D.
`IN SUPPORT OF MODERNA THERAPEUTICS, INC.’S
`PETITIONER’S OPPOSITION TO PATENT OWNER’S
`CONTINGENT MOTION TO AMEND
`
`Mail Stop: PATENT BOARD
`Patent Trial and Appeal Board
`U.S. Patent & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`10656042
`
`
`
`Moderna Ex 1022-p. 1
`Moderna v Protiva
`IPR2018-00739
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`Case No. IPR2018-00739
`U.S. Patent No. 9,364,435
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`
`TABLE OF CONTENTS
`
`Page
`INTRODUCTION .................................................................................. 1
`I.
`SUMMARY OF OPINIONS .................................................................. 2
`II.
`III. QUALIFICATION AND EXPERIENCE .............................................. 2
`IV. LEVEL OF ORDINARY SKILL IN THE ART .................................... 7
`V.
`LEGAL PRINCIPLES............................................................................ 7
`A.
`Claim construction ....................................................................... 7
`B.
`Prior Art........................................................................................ 8
`C. Anticipation .................................................................................. 9
`D. Obviousness ................................................................................. 9
`VI. The Term “Serum Stabile” and the Limitation of Resisting
`Nuclease Degradation Do Not Render The Claims Patentable ............ 14
`The Addition of the Term “Serum-Stable” Is Technically
`A.
`Deficient ..................................................................................... 14
`The Limitation of Resisting Degradation Does Not
`Differentiate the Prior Art .......................................................... 17
`VII. The Narrowed Claimed Concentrations of Lipid Components
`Remain Obvious By A Preponderance of the Evidence ...................... 18
`A. Overlap with the Prior Art Ranges Is Even More
`Pronounced ................................................................................. 18
`Test Data Does Not Demonstrate Unexpected Results
`Commensurate with the Scope of the Claims ............................ 18
`VIII. The Proposed Substitute Claims Lack Written Description
`Support .................................................................................................. 19
`
`B.
`
`B.
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`TABLE OF CONTENTS
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`Page
`
`
`A.
`
`The Written Description in the ’435 Patent Describes
`siRNA Payloads ......................................................................... 19
`B. A POSITA Would Not Consider Patentee To Be In
`Possession of Nucleic-Acid Lipid Particles with a mRNA
`Payload ....................................................................................... 23
`The Board Has Found Comparable Disclosures Lacking .......... 24
`C.
`IX. The Proposed Substitute Claims Lack Enablement ............................. 25
`X.
`CONCLUSION .................................................................................... 26
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`I, Dr. Andrew S. Janoff, PhD, declare as follows:
`I.
`INTRODUCTION
`1. My name is Andrew S. Janoff. I am a consultant in biotechnology
`
`and drug delivery, primarily focusing on lipid and liposome technology. I have
`
`been retained by counsel for Moderna Therapeutics, Inc. (“Moderna”) as an
`
`expert in the relevant art.
`
`2.
`
`I submitted a declaration dated March 5, 2018 in support of
`
`Moderna’s initial Petition for Inter Partes review of U.S. Patent No. 9,364,435
`
`(the “’435 patent”). See EX1007.
`
`3.
`
`On December 21, 2018, Patent Owner Protiva Biotherapeutics,
`
`Inc. (“Patent Owner”) filed its response to Moderna’s petition. I have been
`
`asked to provide additional opinions in response to Patent Owner’s response
`
`that are relevant to Moderna’s reply. My opinions concerning Moderna’s reply
`
`are put forth in a separate declaration.
`
`4.
`
`Also on December 21, 2018, Patent Owner filed its Contingent
`
`Motion to Amend (“MTA”). Patent Owner thereafter filed a Corrected Patent
`
`Owner’s Contingent Motion to Amend on January 30, 2019. I have been asked
`
`to provide additional opinions in response to Patent Owner’s MTA. The
`
`opinions discussed herein are my own.
`
`5.
`
`This declaration is based on the information currently available to
`
`me. To the extent that additional information becomes available, I reserve the
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`right to continue my investigation and study, which may include a review of
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`documents and information that may be produced, as well as testimony from
`
`depositions.
`
`II. SUMMARY OF OPINIONS
`6.
`The issued claims of the ’435 patent cover disparate nucleic acid
`
`payloads, any of a host of potential lipid components, and ranges for lipid
`
`component concentrations for nucleic acid-lipid particles. As written, these
`
`claims overlap with the prior art, including the Patent Owner’s own prior
`
`disclosures rendering them prima facie obvious. The set of substitute claims
`
`presented in Patent Owner’s MTA do not remedy the invalidity issues raised.
`
`The proposed substitute claims purport to add “limitations” to the preamble,
`
`are based upon mischaracterizations of the knowledge in the art, and lack
`
`written description support and an enabling disclosure for the different nucleic
`
`acid payloads recited therein.
`
`III. QUALIFICATION AND EXPERIENCE
`7.
`I am formally trained as a membrane biophysicist. I obtained my
`
`Ph.D. degree in Biophysics from Michigan State University in 1980. Before
`
`that, I received my MS in Biophysics from Michigan State University in 1977,
`
`and my BS in Biology from The American University in 1971. I received
`
`postdoctoral training in Pharmacology at the Harvard Medical School and in
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`Anesthesia at the Massachusetts General Hospital.
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`8.
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`I have played leadership roles in the discipline of pharmaceutical
`
`liposomology from its inception in 1981.
`
`9.
`
`After my post-doctoral work, I was recruited from Harvard by the
`
`industrialist, Jack Whitehead, and became the first senior founding scientist at
`
`the Liposome Company, Inc. I eventually became the Vice President of
`
`Research and Development at the Liposome Company. I led the team at the
`
`Liposome Company that discovered, formulated, and developed ABELCET, a
`
`novel lipid structure that is approved worldwide for systemic fungal infections.
`
`I first published the physical chemical characterization of this structure, along
`
`with an explanation of why it would yield a less toxic alternative to the
`
`traditional micelle formulation in the Proceedings of the National Academy of
`
`Sciences.
`
`10.
`
`I led the team at the Liposome Company that developed Staclot
`
`LA, a diagnostic reagent comprised of Hexagonal (II) lipid that is a standard
`
`practice for diagnosing lupus anticoagulant. The work leading to this product
`
`was also published in the Proceedings of the National Academy of Sciences.
`
`11.
`
`In addition I lead teams at the Liposome Company that formulated
`
`and characterized Myocet (Liposomal Doxorubicn Injection). This product is
`
`currently approved in Canada and the European Union and is used to treat
`
`metastatic breast cancer.
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`12. From 2001-2002, I was Chairman, and from 2002-2005, I was
`
`Chairman and CEO, of Celator Technologies, Inc. I was involved in the
`
`creation of Celator’s intellectual property platform and built the company from
`
`a Canadian start up into an international pharmaceutical corporation with
`
`research, manufacturing, clinical development, regulatory, commercial, and
`
`legal functions. From 2005-2008, I was Chairman and CEO of its successor,
`
`Celator Pharmaceuticals, Inc., a company using controlled-release liposomes to
`
`deliver combinations of chemotherapeutic agents to tumors. Celator’s drug
`
`Vxyeos was recently approved by the FDA for the treatment of leukemia.
`
`13. From 2009-2011, I was CEO of TranslationUP, which was a
`
`consortium of authorities from academic research, drug development, policy,
`
`finance, public relations, and law seeking to create a new model to more
`
`effectively advance government funded late-stage discovery concepts into
`
`clinical development.
`
`14.
`
`In my career, I have overseen the filing of eight INDs, two NDAs
`
`and one MAA in the areas of oncology, antiinfectives, and acute respiratory
`
`distress syndrome, all involving liposome or lipid-delivery systems.
`
`15.
`
`I have worked and published in the area of pulmonary surfactants
`
`involving treatment modalities in which lamellar lipid for instilling into
`
`neonate lungs was constructed to rearrange into the Hexagonal II architecture
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`at body temperature. An article that I published on this topic in Science was
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`reviewed and highlighted in Lancet, a leading British Medical Journal.
`
`16.
`
`I have lectured and have conducted Grand Rounds in the areas of
`
`liposomes, lipid physical chemistry and drug delivery at many prestigious
`
`medical centers in the United States and Canada, and have been invited to
`
`speak on these topics at major industry, financial, scientific and medical
`
`symposia worldwide.
`
`17.
`
`I have also served on various government advisory committees.
`
`For example, I taught at the NATO Advanced Study Institute in Cape Sunion,
`
`Greece, participated in FDA symposia regarding the quality and performance
`
`of controlled release parenterals, served on the Committee of Science and the
`
`Arts at the Franklin Institute in Philadelphia, and was a founding member on
`
`the Scientific Advisory Board at Rider University. I have also advised the
`
`Centre for Drug Research and Development in Vancouver, Canada on
`
`liposomal delivery systems.
`
`18.
`
`I have served as an Adjunct Professor in the Department of
`
`Pathology, Anatomy and Cell Biology at Thomas Jefferson University Medical
`
`School. I have also been a visiting Research Scholar at Princeton University
`
`and have held appointments in the Departments of Physics, Molecular Biology,
`
`and Chemical Engineering.
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`19.
`
`I am the Editor-in-Chief Emeritus of the Journal of Liposome
`
`Research. I served on the editorial board of this Journal from 1994-1997, and
`
`was the Editor-in-Chief from 1997-2008.
`
`20.
`
`I am an editor of Liposomes: Rational Design (Marcel Dekker,
`
`New York, 1999), a volume of expert reviews in the field of liposomology.
`
`21.
`
`I hold over 75 U.S. patents in lipid nanotechnology and drug
`
`delivery, and I have authored more than 90 scientific articles and reviews
`
`principally related to nanotechnology, lipid supramolecular structure,
`
`liposomes, and drug delivery including fusogenic liposomes and triggerable
`
`lipid assemblies.
`
`22. My curriculum vitae was attached as Exhibit 1018.
`
`23.
`
`I am being compensated by Moderna for my time spent in
`
`developing this declaration at a rate of $750 per hour, and for any time spent
`
`testifying in connection with this declaration at a rate of $750 per hour. My
`
`compensation is not contingent upon the substance of my opinion, the content
`
`of this declaration or any testimony I may provide, or the outcome of the inter
`
`partes review or any other proceeding.
`
`24.
`
`I have no financial interest in Moderna.
`
`25. My opinion expressed in this declaration are based on the Petition
`
`and exhibits cited in the Petition, and other documents and materials identified
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`in this declaration, including the ’435 patent (Ex. 1001) and its prosecution
`
`history (Ex. 1016), the prior art references and materials discussed in this
`
`declaration, and any other references specifically identified in this declaration.
`
`26.
`
`I am aware of information generally available to, and relied upon
`
`by, persons of ordinary skill in the art at the relevant times, including technical
`
`dictionaries and technical reference materials (including, for example,
`
`textbooks, manuals, technical papers, articles, and relevant technical
`
`standards).
`
`27.
`
`I reserve the right to supplement my opinions to address any
`
`information obtained, or positions taken, based on any new information that
`
`comes to light throughout this proceeding.
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART
`28.
`I submit that the level articulated by the Board in its Institution
`
`Decision is clear and I agree with it. See EX1007, ¶32.
`
`V. LEGAL PRINCIPLES
`A. Claim construction
`29.
`I have reviewed the Board’s preliminary construction of “nucleic
`
`acid-lipid particle” in the Initial Determination as a “particle that comprises a
`
`nucleic acid and lipids, in which the nucleic acid may be encapsulated in the
`
`lipid portion of the particle.” See EX1001, 11:14–22. I agree with this
`
`construction and that it is appropriate.
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`B.
`30.
`
`Prior Art
`I understand that a patent or other publication must first qualify as
`
`prior art before it can be used to invalidate a patent claim. I understand that a
`
`U.S. or foreign patent qualifies as prior art to an asserted patent if the date of
`
`issuance of the patent is prior to the invention of the asserted patent. I further
`
`understand that a printed publication, such as an article published in a
`
`magazine or trade publication, qualifies as prior art to an asserted patent if the
`
`date of publication is prior to the invention of the asserted patent.
`
`31.
`
`I understand that a U.S. or foreign patent also qualifies as prior art
`
`to an asserted patent if the date of issuance of the patent is more than one year
`
`before the filing date of the asserted patent. I further understand that a printed
`
`publication, such as an article published in a magazine or trade publication,
`
`constitutes prior art to an asserted patent if the publication occurs more than
`
`one year before the filing date of the asserted patent.
`
`32.
`
`I understand that a U.S. patent qualifies as prior art to the asserted
`
`patent if the application for that patent was filed in the United Stated before the
`
`invention of the asserted patent.
`
`33.
`
`I understand that documents and materials that qualify as prior art
`
`can be used to invalidate a patent claim via anticipation or obviousness.
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`C. Anticipation
`34.
`I understand that, once the claims of a patent have been properly
`
`construed, the second step in determining anticipation of a patent claim
`
`requires a comparison of the properly construed claim language to the prior art
`
`on a limitation-by-limitation basis.
`
`35.
`
`I understand that a prior art reference “anticipates” an asserted
`
`claim, and thus renders the claim invalid, if all elements of the claim are
`
`disclosed in that prior art reference, either explicitly or inherently (i.e.,
`
`necessarily present).
`
`36.
`
`I understand that anticipation in an inter partes review must be
`
`shown by a preponderance of the evidence.
`
`D. Obviousness
`37.
`I understand that even if a patent is not anticipated, it is still
`
`invalid if the differences between the claimed subject matter and the prior art
`
`are such that the subject matter as a whole would have been obvious at the time
`
`the invention was made to a person of ordinary skill in the pertinent art.
`
`38.
`
`I understand that a person of ordinary skill in the art at the time
`
`the invention was made provides a reference point from which the prior art and
`
`claimed invention should be viewed. This reference point prevents one from
`
`using his or her own insight or hindsight in deciding whether a claim is
`
`obvious.
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`39.
`
`I also understand that an obviousness determination includes the
`
`consideration of various factors such as (1) the scope and content of the prior
`
`art, (2) the differences between the prior art and the asserted claims, (3) the
`
`level of ordinary skill in the pertinent art, and (4) the existence of secondary
`
`considerations such as commercial success, long-felt but unresolved needs,
`
`failure of others, etc.
`
`40.
`
`I understand that an obviousness evaluation can be based on a
`
`combination of multiple prior art references. I understand that the prior art
`
`references themselves may provide a suggestion, motivation, or reason to
`
`combine, but other times the nexus linking two or more prior art references is
`
`simple common sense. I further understand that obviousness analysis
`
`recognizes that market demand, rather than scientific literature, often drives
`
`innovation, and that a motivation to combine references may be supplied by the
`
`direction of the marketplace.
`
`41.
`
`I understand that if a technique has been used to improve one
`
`device, and a person of ordinary skill in the art would recognize that it would
`
`improve similar devices in the same way, using the technique is obvious unless
`
`its actual application is beyond his or her skill.
`
`42.
`
`I also understand that practical and common sense considerations
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`should guide a proper obviousness analysis, because familiar items may have
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`obvious uses beyond their primary purposes. I further understand that a person
`
`of ordinary skill in the art looking to overcome a problem will often be able to
`
`fit together the teachings of multiple publications. I understand that
`
`obviousness analysis therefore takes into account the inferences and creative
`
`steps that a person of ordinary skill in the art would employ under the
`
`circumstances.
`
`43.
`
`I understand that a particular combination may be proven obvious
`
`merely by showing that it was obvious to try the combination. For example,
`
`when there is a design need or market pressure to solve a problem and there are
`
`a finite number of identified, predictable solutions, a person of ordinary skill in
`
`the art has good reason to pursue the known options within his or her technical
`
`grasp. The result is likely the product not of innovation but of ordinary skill in
`
`the art and common sense.
`
`44. The combination of familiar elements according to known
`
`methods is likely to be obvious when it does no more than yield predictable
`
`results. When a work is available in one field of endeavor, design incentives
`
`and other market forces can prompt variations of it, either in the same field or a
`
`different one. If a person of ordinary skill in the art can implement a
`
`predictable variation, the patent claim is likely obvious.
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`45.
`
`It is further my understanding that a proper obviousness analysis
`
`focuses on what was known or obvious to a person of ordinary skill in the art,
`
`not just the patentee. Accordingly, I understand that any need or problem
`
`addressed by the patent that was known in the field of endeavor at the time of
`
`invention can provide a reason for combining the elements in the manner
`
`claimed.
`
`46.
`
`I understand that a claim can be obvious in light of a single
`
`reference, without the need to combine references, if the elements of the claim
`
`that are not found explicitly or inherently in the reference can be supplied by
`
`the common sense of one of skill in the art.
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`47.
`
`I understand that the disclosure of overlapping ranges in the prior
`
`art establishes a prima facie case of obviousness under 35 U.S.C § 103, but that
`
`a petitioner still has the burden of demonstrating invalidity by the
`
`preponderance of the evidence.
`
`48.
`
`I understand that secondary indicia of non-obviousness may
`
`include (1) a long felt but unmet need in the prior art that was satisfied by the
`
`invention of the patent; (2) commercial success of processes covered by the
`
`patent; (3) unexpected results achieved by the invention; (4) praise of the
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`invention by others skilled in the art; (5) taking of licenses under the patent by
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`others; (6) deliberate copying of the invention; (7) failure of others to find a
`
`solution to the long felt need; and (8) skepticism by experts.
`
`49.
`
`I also understand that there must be a relationship between any
`
`such secondary considerations and the invention. I further understand that
`
`contemporaneous and independent invention by others is a secondary
`
`consideration supporting an obviousness determination.
`
`50.
`
`I understand that unexpected results can support a nonobviousness
`
`determination but must show unexpected results for the entire claimed range.
`
`This can be done by demonstrating that an embodiment has an unexpected
`
`result and providing an adequate basis to support the conclusion that other
`
`embodiments falling within the claim will behave in the same manner.
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`51.
`
`In sum, my understanding is that prior art teachings are properly
`
`combined where a person of ordinary skill in the art having the understanding
`
`and knowledge reflected in the prior art and motivated by the general problem
`
`facing the inventor, would have been led to make the combination of elements
`
`recited in the claims. Under this analysis, the prior art references themselves, or
`
`any need or problem known in the field of endeavor at the time of the
`
`invention, can provide a reason for combining the elements of multiple prior
`
`art references in the claimed manner.
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`52.
`
`I understand that obviousness in an inter partes review must be
`
`shown by a preponderance of the evidence.
`
`VI. The Term “Serum Stabile” and the Limitation of Resisting Nuclease
`Degradation Do Not Render The Claims Patentable
`A. The Addition of the Term “Serum-Stable” Is Technically
`Deficient
`I believe Patent Owner’s amended claims are technically deficient.
`
`53.
`
`Amended claim 21 adds the term “serum-stable” to the preamble, but not to the
`
`body of the claim. MTA, 4. The addition of the limitation regarding resisting
`
`nuclease degradation does not require the particle to be “serum stable” as such
`
`resistance can be tested in vitro using a nuclease. Patent Owner neither relied
`
`on the phrase to define its invention nor is the phrase essential to understand
`
`limitations or terms in the claim body. Therefore, I believe that a POSITA
`
`would not consider the term “serum-stable” limiting in the claims.
`
`54. Even if found limiting, the cited prior art references disclose
`
`serum-stable particles at greater than 50 mol% cationic lipid. Each of the three
`
`primary references disclose the desire for serum-stable particles. EX1002,
`
`[0002] (“serum-stable nucleic acid-lipid particles”), [0015-0016], [0120],
`
`[0134]; EX1003, [0182] (“serum-stable nucleic acid-lipid particles”), [0191],
`
`[0217]; MTA, 15 (“… the ’554 publication stresses that serum-stability is a
`
`critical property of in vivo formulations.” (citing EX1004, [0014], [0015],
`
`[0158])). I also note that each of the references also disclose that the cationic
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`lipid concentrations can be up to 60 mol%. EX1002, [0088], EX1003, [0152],
`
`EX1004, [0116]. In addition, ’189 publication specifically discloses a series of
`
`in vivo experiments detailing efficacy of the 2:40 formulation. EX1003,
`
`[0351]-[0391]. The ’554 publication goes even further detailing a series of in
`
`vivo experiments with formulations having cationic lipid concentrations of 48-
`
`52 mol%. EX1004, [0408], Table IV (L077, L069, L080, L082, L083, L060,
`
`L061, and L051 at 48-52 mol% cationic lipid); Fig. 29 (efficacy of
`
`formulations in vivo). I conclude that a POSITA would understand these
`
`disclosures in the context of the prior art references to disclose serum-stable
`
`particles at greater than 50 mol% cationic lipid.
`
`55. Patent Owner erroneously concludes that the ’196 PCT limits the
`
`cationic lipid mol% to 5-15 for systemic use for all embodiments. MTA, 14.
`
`The ’196 PCT states that “for systemic delivery, the cationic lipid may
`
`comprise from about 5 mol% to about 15 mol%.” EX1001, [0088]. But, this
`
`range limitation is permissive for good reason—it may be appropriate for
`
`certain cationic lipids (e.g., non-ionizable cationic lipids), but unnecessary for
`
`other substantially non-toxic cationic lipids (e.g., ionizable cationic lipids like
`
`DLinDMA).
`
`56.
`
`Indeed it was well-known in the prior art that toxicity in nucleic
`
`acid-lipid particles is largely a function of such particles having a net positive
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`charge. EX1002, [0015] (an overall neutral charge are preferred), EX1003,
`
`[0219] (same); EX1010, 277 (SNALPs developed with “low surface charge
`
`required for systemic delivery”). The potential impact of the amount of cationic
`
`lipid on the net charge of resulting particles depends, among other things, on
`
`whether the cationic lipid carries a positive charge at physiological pH.
`
`57. To address potential toxicity issues, years before the ’435 patent,
`
`ionizable cationic lipids had been developed whose charge was low or
`
`essentially neutral at physiological pH of 7.4. EX1003 [0223] (using
`
`DLinDMA); EX1010, 280 (same), Fig. 1 (showing substantially neutral charge
`
`at pH 7.4). Because of the low charge of such cationic lipids at physiological
`
`pH, higher concentrations of cationic lipid can be used while maintaining a
`
`neutral charge in the resulting particles. EX1003, [0351-0391] (various in vivo
`
`testing for 2:40 formulation using DLinDMA), [0076, 0151] (resulting
`
`particles “substantially non-toxic”).
`
`58. The ’189 publication is instructive. It contains the exact same
`
`permissive language regarding a 5-15 mol% range of cationic lipid for
`
`systemic use found in the ’196 PCT. EX1003, [0152]. The ’189 publication
`
`describes systemic use in in vivo testing using a 2:40 formulation (well above
`
`5-15 mol% range) using the ionizable cationic lipid DLinDMA. Id., [0351-
`
`0391].
`
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`59. The identified L054 formulation was used in in vitro testing and
`
`contained the cationic lipid, DMOBA. Patent Owner asserts that DMOBA is
`
`too toxic for systemic use at a higher cationic lipid concentrations. MTA, 16.
`
`Patent Owner ignores the disclosure in the ’554 publication that 52 mol%
`
`DMOBA showed in vivo efficacy. EX1004, Table IV (L060 formulation);
`
`[0408] (testing); Fig. 29 (results).
`
`B.
`
`The Limitation of Resisting Degradation Does Not
`Differentiate the Prior Art
`60. Testing for resistance to nuclease degradation by exposure to
`
`nucleases for 20 min at 37°C was commonplace. I believe that a POSITA
`
`would have been aware of such testing, especially given the express disclosures
`
`in Patent Owner’s prior disclosures. Patent Owner erroneously states that the
`
`prior art “does not disclose nucleic acid-lipid particles formulated for systemic
`
`use that can withstand nuclease exposure for 20 min at 37°C.” MTA at 17.
`
`Each of the three primary references disclose nucleic acid-lipid particles that
`
`can also withstand nuclease exposure and Patent Owner’s prior disclosures
`
`disclose these exact parameters. EX1002, cl.2 [0011] (“… the nucleic acid in
`
`the nucleic acid-lipid particle is resistant in aqueous solution to degradation by
`
`a nuclease.”), [0085], [0174], [0204] (stability tested at 37 degrees for 30
`
`minutes); EX1003, cl. 31 (“… the nucleic acid in said nucleic acid-lipid
`
`particle is not substantially degraded after exposure of said particle to a
`
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`nuclease at 37° C. for 20 minutes.”), [0013] (nuclease resistance for “at least
`
`30, 45, or 60 minutes” at 37°C), [0076], [0151], [0248]; EX1004, [0020],
`
`[0210], [0261], [0268] (“… chemically modified nucleotides present in the
`
`single stranded siRNA molecules of the invention are preferably resistant to
`
`nuclease degradation ….”), [0299], [0514], [0522-0523]. I believe that a
`
`POSITA would have been aware of the test procedures disclosed in this
`
`limitation.
`
`61. Patent Owner points to an irrelevant paragraph in an unrelated
`
`reference for the ’196 PCT (EX1008 (Goa)) and fails to address the ’189
`
`publication at all. MTA, 18. Regarding the ’554 publication, Patent Owner
`
`ignores the disclosure that testing was done on modified nucleic acid
`
`constructs, for example with a construct containing siRNA, to show “nuclease
`
`stability for systemic administration in vivo ….” EX1004, [0578]; MTA, 18.
`
`VII. The Narrowed Claimed Concentrations of Lipid Components
`Remain Obvious By A Preponderance of the Evidence
`A. Overlap with the Prior Art Ranges Is Even More Pronounced
`62. The prior art discloses concentration of cationic lipids that overlap
`
`an even greater proportion of the ranges in the substitute claims.
`
`B.
`
`63.
`
`Test Data Does Not Demonstrate Unexpected Results
`Commensurate with the Scope of the Claims
`I do not believe that Patent Owner demonstrated unexpected
`
`results for the entire claimed range to support patentability. The cited test data
`
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`is not coextensive with the claimed range—claim 21 covers any payload and
`
`any lipid components to make nucleic-acid lipid particles using any
`
`formulation process. Patent Owner points to testing of only siRNA payloads
`
`with a limited number of exemplar lipid components and with limited
`
`formulation processes.
`
`64. Contrary to Patent Owner’s assertions, Patent Owner’s expert
`
`admitted that the test data did not show the claimed formulations
`
`outperforming the prior art 2:40 formulation. EX1019, 183:22-184:13 (“[s]ome
`
`are better, some are similar.”).
`
`65. Third, Patent Owner cites to later testing that confirms that the
`
`1:57 formulation is ineffective with various cationic lipids. Ex. 2017, Fig. 2;
`
`Ex. 2018, Figs. 1-3. A fact that Patent Owner’s expert confirmed: “cationic
`
`lipids using 1:57 formulation “have similar knockdown levels as--as PBS.”
`
`EX1020, 401:6-21; see also id. 393:21:394:24 (1:57 formulation with DLin
`
`morph shows no efficacy). Given these deficiencies, I conclude that the test
`
`data does not demonstrate unexpected results commensurate with the scope of
`
`the claims.
`
`VIII. The Proposed Substitute Claims Lack Written Description Support
`A. The Written Description in the ’435 Patent Describes siRNA
`Payloads
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`66.
`
`In gene therapy, a variety of nucleic acid payloads can be used,
`
`e.g., siRNA or mRNA. EX1001, 10:26-67. The sizes of these different
`
`nucleotides can vary dramatical
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