Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 1 of 820 PageID #: 7487
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 1 of 820 PagelD #: 7487
`
`JOINT APPENDIX 23
`JOINT APPENDIX 23
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 2 of 820 PageID #: 7488
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 2 of 820 PagelD #: 7488
`
`I hereby certify that this correspondenceis being filed via
`PATENT
`EFS-Webwith the United States Patent and Trademark Office
`AOT1dTAO
`.
`
`December 14.2015 Attorney Docket No.: 086399-001220US-091 1148
`on
`
`KILPATRICK TOWNSEND & STOCKTON LLP
`
`By:
`
`__/Judith Cotham/
`Judith Cotham
`
`IN THE UNITED STATES PATENT AND TRADEMARKOFFICE
`
`In re application of:
`
`Confirmation No. 1042
`
`Tan MacLachlanetal.
`
`Examiner;
`
`Hirt, Erin E.
`
`Application No.: 14/304,578
`
`Art Unit:
`
`1616
`
`Filed: June 13, 2014
`
`AMENDMENT
`
`For: LIPID COMPOSITIONS FOR
`NUCLEIC ACID DELIVERY
`
`Customer No.: 20350
`
`
`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Commissioner:
`
`In response to the Office Action mailed October 9, 2015, please enter the
`
`following amendments and remarks.
`
`Amendments to the Claimsarereflected in thelisting of claims which begins on
`
`page 2 of this paper.
`
`Remarksbegin on page 4 ofthis paper.
`
`Page 1 of 7
`
`JA00674
`GENV-00011429
`
`JA00674
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 3 of 820 PageID #: 7489
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 3 of 820 PagelD #: 7489
`
`Appl. No. 14/304,578
`Amdt. dated December 14, 2015
`Reply to Office Action of October 9, 2015
`
`Amendments to the Claims:
`
`PATENT
`
`Thislisting of claims will replace all prior versions, andlistings of claimsin the application:
`
`Listing of Claims:
`
`
`
`l. (Currently amended)Alipid vesicle formulation comprising:
`
`~~HNNFFSPWYWN
`
`(a) a plurality of lipid vesicles, wherein each lipid vesicle comprises:
`
`a cationic lipid;
`
`an amphipathic lipid; and
`
`a polyethyleneglycol (PEG)-lipid; and
`(b) messenger RNA (mRNA), whereinat least 70% [[50%]] of the mRNAin the
`
`formulationis fully encapsulated in the lipid vesicles.
`
`2.
`
`(Previously presented) Thelipid vesicle formulation of claim 1, wherein
`
`the amphipathic lipid is a phospholipid.
`
`3.
`(Previously presented) The lipid vesicle formulation of claim 2, wherein
`the phospholipid is selected from the group consisting of phosphatidylcholine,
`phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid,
`palmitoyloleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine,
`dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, distearoylphosphatidylcholine,
`
`and dilinoleoylphosphatidylcholine.
`
`4.
`
`. (Previously presented) The lipid vesicle formulation of claim 1, wherein
`
`eachlipid vesicle further comprisesa sterol.
`
`5.
`
`(Previously presented) The lipid vesicle formulation of claim 4, wherein
`
`the sterol is cholesterol.
`
`6.
`
`(Previously presented) The lipid vesicle formulation of claim 4, wherein
`
`the sterol is cholesterol and the amphipathiclipid is a phospholipid.
`
`Page 2 of 7
`
`JA00675
`GENV-00011430
`
`JA00675
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 4 of 820 PageID #: 7490
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 4 of 820 PagelD #: 7490
`
`Appl. No. 14/304,578
`Amdt. dated December 14, 2015
`Reply to Office Action of October 9, 2015
`
`PATENT
`
`NHoOSPWNH
`
`—
`
`7.
`
`(Previously presented) Thelipid vesicle formulation of claim 6, wherein
`
`the phospholipid is selected from the group consisting of phosphatidylcholine,
`
`phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid,
`
`palmitoyloleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine,
`
`dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, distearoylphosphatidylcholine,
`
`and dilinoleoylphosphatidylcholine.
`
`8.
`
`(Previously presented) The lipid vesicle formulation of claim 1, wherein
`
`each lipid vesicle is a liposome.
`
`9.
`
`(Previously presented) The lipid vesicle formulation of claim 1, wherein
`
`each lipid vesicle is a lipid-nucleic acid particle.
`
`10.
`
`(Previously presented) Thelipid vesicle formulation of claim 1, wherein
`
`each lipid vesicle is about 150 nm orless in diameter.
`
`11.
`
`(Previously presented) The lipid vesicle formulation of claim 1, wherein
`
`the cationic lipid only carries a positive charge at below physiological pH.
`
`12.
`
`(Previously presented) Thelipid vesicle formulation of claim 1, wherein
`
`each lipid vesicle is about 100 nm orless in diameter.
`
`13.
`
`14.
`
`(Canceled)
`
`(Previously presented) Thelipid vesicle formulation of claim 1, wherein
`
`at least 80% of the mRNAin the formulation is fully encapsulated in thelipid vesicles.
`
`15.
`
`(Previously presented) Thelipid vesicle formulation of claim 1, wherein
`
`about 90% of the mRNAin the formulation is fully encapsulated in the lipid vesicles.
`
`Page 3 of 7
`
`JA00676
`GENV-00011431
`
`JA00676
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 5 of 820 PageID #: 7491
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 5 of 820 PagelD #: 7491
`
`Appl. No. 14/304,578
`Amdt. dated December 14, 2015
`Reply to Office Action of October 9, 2015
`
`PATENT.
`
`REMARKS
`
`I.
`
`STATUS OF THE CLAIMS
`Upon entry of this amendment, claims 1-12, 14, and 15 are pending in this
`application andare presented for examination. Claim 1 has been amended. Support is found, for
`example, in previous claim 13, now canceled. As such, no new matter has been introduced.
`Based on the following remarks, Applicants respectfully request reconsideration and allowance
`
`of the pending claims.
`
`IT.
`
`DOUBLE PATENTING REJECTIONS
`Claims 1, 9, and 10 were rejected on the ground of nonstatutory obviousness-type
`double patenting over claims 1, 9, 10, 17, and 19 of U.S. Patent No. 8,058,069. Claims 1-7, 9,
`and 10 were rejected on the ground of nonstatutory obviousness-type double patenting over
`claims 1, 4-6, 12, and 21 of U.S. Patent No. 8,283,333. Claims 1 and 9 were rejected on the
`ground of nonstatutory obviousness-type double patenting over claims 1, 4, 10, and 18 of U.S,
`Patent No. 7,799,565.
`Claims 1-7 and 9 were rejected on the ground of nonstatutory
`obviousness-type double patenting over claims 1-6, 8, 10, and 11 of U.S. Patent No. 8,466,122.
`Claims 1-3 and 9 wererejected on the groundof nonstatutory obviousness-type double patenting
`over claims 1, 8, 14, and 20 of U.S. Patent No. 8,492,359.
`In an earnest effort to expedite prosecution, but without acquiescing on the merits
`of the present rejections, claim 1 has been amendedto include the feature of claim 13. Notably,
`Applicants point out that claim 13 is not part of the present rejections. Therefore, Applicants
`respectfully request that the Examiner withdraw the present obviousness-type double patenting
`
`rejections.
`
`lil.
`
`REJECTION UNDER35 U.S.C. § 103(a)
`Claims 1~15 were rejected under 35 U.S.C. § 103(a) as allegedly being obvious
`over Saravolac et al, (US Patent No. 6,734,171) and Yoshiokaet al. (US Patent No. 5,593,622),
`
`Applicants respectfully traverse.
`In the Office Action, the Examineralleges that it would have been obvious to one
`of ordinary skill in the art to make liposomes comprising the same components as presently
`
`Page 4 of 7
`
`JA00677
`GENV-00011432
`
`JA00677
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 6 of 820 PageID #: 7492
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 6 of 820 PagelD #: 7492
`
`Appl. No. 14/304,578
`Amdt. dated December14, 2015
`Reply to Office Action of October 9, 2015
`
`PATENT
`
`claimed because Saravolac et al. teaches that it was known in the art to make liposomes and
`
`lipid-nucleic acid particles from cationic lipids, PEG-lipids, a sterol, and fusogenic lipids which
`allow for increased encapsulation efficiencies of over 80%, specifically up to about 86%. See,
`
`Office Action at page 8.
`In response, Applicants respectfully submit herewith a Declaration of Dr. James
`Heyes under 37 C.F.R. § 1.132 (hereinafter, “Heyes Declaration”) to present evidence that the
`method described in Saravolac et al. for preparing lipid particles containing plasmid DNAis not
`suitable for producing the populationof lipid vesicles with an mRNA encapsulationefficiency as
`
`presently claimed.
`As explained by Dr. Heyes in his Declaration, he and his colleagues used the
`method for preparing lipid particles containing plasmid DNA described in Example 1 of
`Saravolac et al.
`to determine the suitability of this method for formulating mRNA in lipid
`
`vesicles. See, Heyes Declaration {ff 8-11.
`Based on the results of the experiment (see, Heyes Declaration 4] 12 & 13), Dr.
`Heyes states that the method for preparing lipid particles described in Saravolac etal. is not
`suitable for producing the population oflipid vesicles with an mRNAencapsulationefficiency as
`presently claimed, wherein at least 70% of the mRNAin the formulation is fully encapsulated in
`the lipid vesicles. See, Heyes Declaration 414. Indeed, Dr. Heyespoints out that they were only
`able to achieve up to 53% encapsulation of the mRNA payload following the method of
`Saravolac ef al., despite using the exact dialysis buffer conditions for obtaining “optimum
`formulations” as described by Saravolac et al.
`See,
`id.
`Furthermore, given the high
`polydispersity indexes of the lipid particles, they were unable to produceparticles of reasonable
`homogeneity using the method described in Saravolac et al. See,
`id. As a result, based on this
`experiment, Dr. Heyes explains that the method ofSaravolacef al. produced a populationoflipid
`particles with a heterogeneous size distribution and that encapsulated only about half of the
`starting mRNA payload.
`See,
`id Moreover, based on Tekmira Pharmaceuticals’ clinical
`experience, and the scientific literature, Dr. Heyes notes that the lipid particles produced by the
`method of Saravolac et al. might invoke an unwanted innate immune response upon systemic
`administration to a human being. See, id Thus, Dr. Heyes concludes that the method described
`
`Page 5 of 7
`
`JA00678
`GENV-00011433
`
`JA00678
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 7 of 820 PageID #: 7493
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 7 of 820 PagelD #: 7493
`
`Appl. No. 14/304,578
`Amdt. dated December14, 2015
`Reply to Office Action of October 9, 2015
`
`PATENT
`
`in Saravolac et al. is not amenable to the productionofthe population of lipid vesicles claimed
`
`in the present application. See, id.
`Forthe foregoing reasons, Dr. Heyes submits that there is no motivation for one
`of ordinary skill in the art to take the teaching of Saravolac et al. and makea lipid vesicle
`formulation using mRNA anda specific combination of lipid components with any reasonable
`expectation that at
`least 70% of the mRNA in the formulation would be successfully
`encapsulated in the lipid vesicles. See, Heyes Declaration J15. In fact, Dr. Heyes points out that
`none of the examples in Saravolac ef al. discloses or suggests a lipid vesicle formulation of the
`present invention comprising fully encapsulated mRNAorthe desirability of forming more
`homogeneousparticle populations that are more effective at delivering encapsulated nucleic acid
`molecules such as mRNAto living cells and thus more desirable for in vivo and clinical
`applications. See,
`id.
`Indeed, the experiment described in the Heyes Declaration clearly shows
`that the method for preparing lipid particles described in Saravolac et al.
`is not suitable for
`formulating the population oflipid vesicles with an mRNAencapsulation efficiency as presently
`
`claimed. See, id.
`Applicants assert that the teaching of Yoshioka ef al. does not remedy the
`deficiencies in the disclosure of Saravolac ef al.
`In fact, Yoshioka et al. fails to provide any
`teaching whatsoever with regard to mRNAorthe successful encapsulation and delivery thereof.
`Indeed, the Examiner merely relies on Yoshiokaet al. for teaching the selection of cholesterol
`and certain phospholipids for inclusion in the lipid particles of Saravolac et al. See, Office
`
`Action at pages 7-8.
`In view of the foregoing, Applicantsassert that the cited references, whether alone
`or in combination, do not teach or suggest each ofthe features recited in the instant claims and
`thusfail to support a legal conclusion of obviousness. Indeed, none of these references discloses
`or suggests a lipid vesicle formulation of the present invention comprising a plurality of lipid
`vesicles and mRNA, wherein at least 70% of the mRNAin the formulation is fully encapsulated
`in the lipid vesicles. To the contrary, Applicants have provided sufficient objective evidence in
`the Heyes Declaration to demonstrate that the method described in Saravolac ef al. for preparing
`lipid particles is simply not suitable for producing the population of lipid vesicles with an
`
`Page 6 of 7
`
`JA00679
`GENV-00011434
`
`JA00679
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 8 of 820 PageID #: 7494
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 8 of 820 PagelD #: 7494
`
`Appl. No. 14/304,578
`Amdt, dated December 14, 2015
`Reply to Office Action of October 9, 2015
`
`PATENT
`
`mRNAencapsulation efficiency as presently claimed. The teaching of Yoshioka ef al. does not
`remedy this deficiency in the method of Saravolac ef al. Accordingly, Applicants respectfully
`request that the Examiner withdraw the presentrejection under 35 U.S.C. § 103(a).
`
`CONCLUSION
`
`In view of the foregoing, Applicants believe all claims now pending in this
`
`application are in condition for allowance. The issuance of a formal Notice of Allowance at an
`
`early date is respectfully requested.
`If the Examiner believes a telephone conference would expedite prosecution of
`
`this application, please telephone the undersigned at 925-472-5000.
`
`Respectfully submitted,
`
`‘Joe C. Hao/
`
`Joe C. Hao
`Reg. No. 55,246
`
`KILPATRICK TOWNSEND & STOCKTON LLP
`Two Embarcadero Center, Eighth Floor
`San Francisco, California 94111-3834
`Tel: 925-472-5000
`Fax: 415-576-0300
`Attachments
`JCH
`
`Page 7 of 7
`
`JA00680
`GENV-00011435
`
`JA00680
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 9 of 820 PageID #: 7495
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 9 of 820 PagelD #: 7495
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`Confirmation No, 1042
`
`lan MacLachlan et al.
`
`Examiner:
`
`Hirt, Erin E.
`
`Application No.: 14/304,578
`
`Art Unit:
`
`1616
`
`Filed: June 13, 2014
`
`DECLARATION UNDER37 C.F.R. § 1.132
`
`For: LIPID COMPOSITIONS FOR
`NUCLEIC ACID DELIVERY
`
`Customer No.: 20350
`
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`I, James Heyes, Ph.D., being duly warned that willful false statements and the like
`
`are punishable by fine or imprisonmentor both, under 18 U.S.C. § 1001, and may jeopardize the
`
`validity of the patent application or any patent issuing thereon, state and declare as follows:
`
`1.
`
`All statements herein made of my own knowledgeare true, and statements
`
`made on mformation or belief are believed to be true and correct.
`
`2
`
`I hold a Ph.D. (2001) in Medicinal Chemistry from the Institute of Cancer
`
`Research (Surrey, UK).
`
`I am presently the Director of Formulation Chemistry at Arbutus
`
`Biopharma Corporation (Burnaby, Canada),
`
`formerly known as Tekmira Pharmaceuticals
`
`Corporation. The assignee of the above-referenced application, Protiva Biotherapeutics Inc., is a
`
`wholly-owned subsidiary of Arbutus Biopharma.
`
`3.
`
`My expertise lies in the developmentoflipid particle formulations and the
`
`design of novel compounds as components oflipid particles. A copy of my Curriculum Vitae is
`
`of record.
`
`JA00681
`GENV-00011436
`
`JA00681
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 10 of 820 PageID #: 7496
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 10 of 820 PagelD #: 7496
`
`Application No. 14/304,578
`Declaration of James Heyes, Ph.D.
`
`Ihave reviewed the above-referenced patent application, and I am familiar
`4,
`with the contents therein.
`I have also reviewed the contents of the Office Action dated October
`
`9, 2015.
`
`The present inventionis directed to a lipid vesicle formulation comprising:
`5,
`(a) a plurality of lipid vesicles, wherein each lipid vesicle comprises:
`a cationic lipid; an
`amphipathic lipid; and a polyethyleneglycol (PEG)-lipid; and (b) messenger RNA (mRNA),
`wherein at least 70% of the mRNAin the formulationis fully encapsulated in the lipid vesicles.
`
`6.
`In the Office Action, the Examinerrelies on Saravolac et al. (US Patent
`No. 6,734,171) in alleging that it would have been obvious to one of ordinary skill in the art to
`make liposomes comprising the same componentsas presently claimed because Saravolacef al.
`teaches that it was known in the art to make liposomes and lipid-nucleic acid particles from
`cationic lipids, PEG-lipids, a sterol, and fusogenic lipids which allow for increased encapsulation
`efficiencies of over 80%, specifically up to about 86%. See, Office Action at page 8.
`
`I submit this Declaration to present evidence that the method described in
`7.
`for preparing lipid particles containing plasmid DNA is not suitable for
`Saravolac et al.
`producing the population oflipid vesicles with an mRNAencapsulation efficiency as presently
`claimed that is desirable for in vivo and clinical applications.
`
`My colleagues and I used the method for preparing lipid particles
`8.
`containing plasmid DNA described in Example | of Saravolac eta/. to determine the suitability
`of this method for formulating mRNA in lipid vesicles.
`
`9,
`The method described. in Saravolac et al. was followed, except for a
`single, minor modification in preparing the lipid stock solutions that,
`to the best of my
`knowledge and belief, is unlikely to affect the outcome of the experiment described herein.
`In
`
`particular,
`
`lipids were dissolved in 100% chloroform,
`
`instead of absolute ethanol, 2:1
`
`chloroform:methanol, or 9:1 benzene:methanol as described in Saravolac et ai. See, col. 21,
`lines 32-34, Since this solvent is evaporated after aliquoting the lipids, and prior to formulating
`
`JA00682
`GENV-00011437
`
`JA00682
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 11 of 820 PageID #: 7497
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 11 of 820 PagelD #: 7497
`
`Application No. 14/304,578
`Declaration of James Heyes, Ph.D.
`
`the particles, to the best of my knowledge and belief, the use of 100% chloroform has no effect
`
`on the process, as the chloroform fully dissolves the lipids and is evaporated afterward.
`
`10,
`
`‘In addition, Saravolacet a/. notes that “optimum formulations are obtained
`
`with 150 mM NaPO,, pH 7.4 with 150 to 175 mM NaCI”in the dialysis buffer, See, col, 21,
`
`lines 55-56. We therefore performed the experiment with both the lower (150 mM) and upper
`
`(175 mM)concentration of NaCl in the dialysis buffer, andthe results of both formulations are
`
`described below.
`
`11.
`
`The experiment was performed as follows:
`
`Preparation of Lipid Particles: DOPE, DODAC, and PEGooo0-CerC8 individual
`
`stock solutions were prepared at 100 mg/mL in chloroform. Aliquots were combined to give a
`
`These were prepared in
`molar ratio of DOPE:DODAC:PEG-CerC8 (42.5:42.5:15 mol%).
`duplicate, and tubes placed under a stream of N2 to evaporate off the solvent. Finally, they were
`
`exposed to vacuum to remove any trace amounts of the chloroform remaining. To the dried lipid
`
`film was added 100 pL of | M octyl glucopyranoside (OGP), 200 pL of 1.0 mg/mL luciferase
`
`mRNA, and 700 uL of PBS buffer containing either 150 mM or 175 mM NaCl. The tubes were
`
`then vigorously vortexed to solubilize the lipid films. Upon complete solubilization,
`
`the
`
`mixtures were transferred to dialysis tubing (3 mL Slide-A-Lyzers with MWCO of 10,000) and
`
`the first sample was dialyzed against 150 mM NaPO,, 150 mM NaCl, pH 7.4, while the other
`
`was dialyzed against 150 mM NaPOsa, 175 mM NaCl, pH7.4. Samples were dialyzed against
`
`1.5 L of dialysis buffer over a 24 hour period with 2 changes of buffer over this time. Upon
`completion of dialysis, the samples were removed from the dialysis bags and analyzed for size
`and percent encapsulation.
`
`12.
`
`Upon completion ofdialysis, the formulations were assessed. Theresults
`
`of the experiment are summarized in Table 1. Three formulation parameters were measured,
`
`each in duplicate:
`
`the amount of mRNA that has been
`e % Encapsulation of mRNA (i.e,
`successfully encapsulated in the particle);
`
`JA00683
`GENV-00011438
`
`JA00683
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 12 of 820 PageID #: 7498
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 12 of 820 PagelD #: 7498
`
`Application No. 14/304,578
`Declaration of James Heyes, Ph.D.
`
`®
`e
`
`Particle size; and
`Polydispersity (i.e., a measure of the heterogeneity of sizes of particles in a
`mixture).
`
`Dialysis Buffer Replicate|Diameter (nm index (PDI) % Encapsulation
`
`
`
`Table |. Size of particles and encapsulation ofmRNA following dialysis
`
`
`tatatac|SS[ta
`
`
`
`
`150mMNaPO,, 150mM.NaCl, 1}
`
`
`
`150mMNaPOs, 175mMNaCl, 2}8ft
`
`
`pH 7.4po2|oeTam
`
`
`
`
`pH 7.4
`
`13.
`
`Similar results were obtained for both formulations containing different
`
`NaCl concentrations.
`
`In particular, a numberof clear deficiencies in the lipid particles prepared
`
`by the method described in Saravolac et al. were observed for both formulations. First, only
`
`about half of themRNA payload was successfully encapsulated into lipid particles. Second, the
`
`polydispersity index (PDI) was high (0.26-0.35). This measurement reflects how homogeneous
`
`a formulation is from a size perspective, with a lower number (i.e, PDI ~0.1 or less) being
`
`desirable and reflecting a more homogeneous particle population. A PDI value around 0.3
`
`indicates a broad range ofparticle sizes in the mixture, which is extremely undesirable in a lipid
`
`particle delivery system. The substantial amount of unencapsulated mRNA and the high
`polydispersity index together or individually increase the likelihood of an unwanted immune
`response upon in vivo administration of the lipid particles,
`
`14.
`
`This experiment demonstrates that the method for preparing lipid particles
`
`described in Saravolacef al. is not suitable for producing the population of lipid vesicles with an
`
`mRNA encapsulation efficiency as presently claimed, wherein at least 70%of themRNAin the
`
`formulation is fully encapsulated in the lipid vesicles.
`
`Indeed, we were only able to achieve up
`
`to 53% encapsulation of the mRNA payload following the method of Saravolac et a/., despite
`
`using the exact dialysis buffer conditions for obtaining “optimum formulations” as described by
`
`Saravolac et al. Furthermore, given the high polydispersity indexes ofthe lipid particles, we
`
`JA00684
`GENV-00011439
`
`JA00684
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 13 of 820 PageID #: 7499
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 13 of 820 PagelD #: 7499
`
`Application No. 14/304,578
`Declaration of James Heyes, Ph.D.
`
`were unable to produce particles of reasonable homogeneity using the method described in
`
`Saravolac ef al. Thus, based on the experiment reported herein, the method of Saravolac et al.
`
`produced a population of lipid particles with a heterogeneous size distribution and that
`
`encapsulated only about half of
`
`the starting mRNA payload.
`
`Based on Tekmira
`
`Pharmaceuticals’ clinical experience, and the scientific literature, the lipid particles produced by
`
`the method of Saravolac et al.
`
`reported herein might
`
`invoke an unwanted innate immune
`
`response upon systemic administration to a human being. Basedon this experiment, | conclude
`
`that the method described in Saravolac et ai. is not amenable to the production of the population
`
`of lipid vesicles claimed in the present application.
`
`15.
`
`For the foregoing reasons, I submit that there is no motivation for one of
`
`ordinary skill
`
`in the art
`
`to take the teaching of Saravolac et af. and make a lipid vesicle
`
`formulation using mRNA and a specific combination of lipid components with any reasonable
`
`expectation that at
`
`least 70% of the mRNA in the formulation would be successfully
`
`encapsulated in the lipid vesicles.
`
`In fact, none of the examples in Saravolac et al. discloses or
`
`suggests a lipid vesicle formulation of the present
`
`invention comprising fully encapsulated
`
`mRNA or the desirability of forming more homogeneous particle populations that are more
`
`effective at delivering encapsulated nucleic acid molecules such as mRNAto living cells and
`
`thus more desirable for in vive and clinical applications.
`
`Indeed, our experiment clearly shows
`
`that the method for preparing lipid particles described in Saravolac et a/.
`
`is not suitable for
`
`formulating the population of lipid vesicles with an mRNA encapsulation efficiency as presently
`
`claimed.
`
`pR
`
`my
`:
`Hec +
`Date
`
`16.
`
`ome
`LAO iD
`
`The declarant has nothing further to say.
`f
`en
`
`
`Ly
`if
`James Heyes, Phd:
`
`JA00685
`GENV-00011440
`
`JA00685
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 14 of 820 PageID #: 7500
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 14 of 820 PagelD #: 7500
`
`JOINT APPENDIX 24
`JOINT APPENDIX 24
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 15 of 820 PageID #: 7501
`Page 15 of 820 PagelD #: 7501
`
`
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and TrademarkOffice
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`www usplo.gov
`
`
`
`
`CONFIRMATIONNO.
`
`APPLICATION NO.
`
`14/304,578
`
`ING DATE
`
`06/13/2014
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`Tan MacLachlan
`
`86399-001220US-9 11148
`
`04/15/2016
`7590
`20350
`KILPATRICK TOWNSEND & STOCKTON LLP
`TWO EMBARCADERO CENTER
`EIGHTH FLOOR
`SAN FRANCISCO, CA 94111-3834
`
`.
`
`
`
`
`HIRT, ERIN E
`
`1616
`
`NOTIFICATION DATE
`
`DELIVERY MODE
`
`04/15/2016
`
`ELECTRONIC
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
`following e-mail address(es):
`ipefiling @kilpatricktownsend.com
`jihice @kilpatrick.foundationip.com
`
`PTOL-90A (Rev. 04/07)
`
`JA00686
`GENV-00011444
`
`JA00686
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 16 of 820 PageID #: 7502
`~ase
`1:22-cv-00252-MSG Document
`181-
`iled 01/03/24
`Page
`16
`of 820 Page!lD #:
`750
`Application No.
`“Applicant(s)
`°
`14/304,578
`MACLACHLAN ETAL.
`
`Examiner
`Art Unit
`AIA (Firstinventor to File)
`ERIN HIRT
`1616
`StatusNo
`
`-- The MAILING DATEof this communication appears on the cover sheet with the correspondence address --
`Period for Reply
`
`Office Action Summary
`
`A SHORTENED STATUTORY PERIOD FOR REPLYIS SET TO EXPIRE 3 MONTHS FROM THE MAILING DATE OF
`THIS COMMUNICATION.
`Extensions of time may be available under the provisions of 37 CFR 1.136(a)
`after S1X (6) MONTHS from the mailing date of this communication.
`If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this communication.
`Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
`Any reply received by the Office later than three monthsafter the mailing date of this communication, evenif timely filed, may reduce any
`earned patent term adjustment. See 37 CFR 1.704{b}.
`
`-
`-
`
`.
`
`Inno event, however, may a reply be timely filed
`
`Status
`1) Responsive to communication(s) filed on 12/14/15.
`1] A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/werefiled on
`2a)lX| This action is FINAL.
`2b)L] This action is non-final.
`3) Anelection was made bythe applicant in responsetoarestriction requirementset forth during the interview on
`; the restriction requirement and election have been incorporated into this action.
`4)L] Since this application is in condition for allowance except for formal matters, prosecution as to the merits is
`closed in accordancewith the practice under Ex parte Quayle, 1935 C.D. 11, 453 O.G. 213.
`
`
`
`Disposition of Claims*
`
`5)D<] Claim(s) 1-12.14 and 15 is/are pending in the application.
`
`5a) Of the above claim(s)
`is/are withdrawn from consideration.
`6)L] Claim(s) ___ is/are allowed.
`
`7)—] Claim(s) 1-12.14 and 15 is/are rejected.
`8)L] Claim(s)____ is/are objectedto.
`
`9)L] Claim(s)
`are subject to restriction and/or election requirement.
`* lf any claims have been determined allowable, you may be eligible to benefit from the Patent Prosecution Highway program at a
`
`participating intellectual property office for the corresponding application. For more information, please see
`htto
`/Avww.uspto.cov/catents/init events/pph
`
`
`
`
`/index.isp or send an inquiry to PPHfeedback@uspto.gov.
`
`Application Papers
`10) The specification is objected to by the Examiner.
`11) The drawing(s)filed on
`is/are: a)L] accepted or b)] objected to by the Examiner.
`Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a).
`
`Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121(d).
`
`Priority under 35 U.S.C. § 119
`12)] Acknowledgmentis made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`Certified copies:
`a)L] All
`b)[-] Some** c)[] None ofthe:
`1.1] Certified copies of the priority documents have been received.
`2 Certified copies of the priority documents have been received in Application No.
`3.L] Copiesof the certified copies of the priority documents have been receivedin this Nationa! Stage
`application from the International Bureau (PCT Rule 17.2(a)).
`™ See the attached detailed Office action for a list of the certified copies not received.
`
`Attachment(s)
`1) CJ Notice of References Cited (PTO-892)
`.
`:
`2) C] Information Disclosure Statement(s) (PTO/SB/08a and/or PTO/SB/08b)
`Paper No(s)/Mail Date
`.
`U.S. Patent and Trademark Office
`PTOL-326 (Rev. 11-13)
`
`Office Action Summary
`
`3) | interview Summary (PTO-413)
`Paper No(s)/Mail Date.
`4 Oo Other:
`ther:
`)
`
`Part of Paper No./Mail Date 20160404
`
`JA00687
`GENV-00011445
`
`JA00687
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 17 of 820 PageID #: 7503
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 17 of 820 PagelD #: 7503
`
`Application/Control Number: 14/304,578
`Art Unit: 1616
`
`Page 2
`
`The present application is being examined under the pre-AlA first to invent
`
`provisions.
`
`DETAILED ACTION
`
`Status of Action
`
`The examiner acknowledgesreceipt of Amendments/Remarksfiled on 12/14/15.
`
`Currently claims 1-12, 14-15 are pending in this application. Claim 13 was canceled.
`
`Status of Claims
`
`Accordingly, claims 1-12 and 14-15 are presented for examination on the merits
`
`for patentability. Rejection(s) not reiterated from the previous Office Action are hereby
`
`withdrawn. The following rejections are either reiterated or newly applied. They
`
`constitute the complete set of rejections presently being applied to the instant
`
`application.
`
`Claim Rejections - 35 USC § 103
`
`The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all
`
`obviousnessrejections set forth in this Office action:
`
`(a) A patent may not be obtained though the invention is not identically disclosed or described as set
`forth in section 102 ofthis title, if the differences between the subject matter sought to be patented 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 having ordinary skill in the art to which said subject matter pertains.
`Patentability shall not be negatived by the manner in which the invention was made.
`
`The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148
`
`USPQ 459 (1966), that are applied for establishing a background for determining
`
`obviousness under 35 U.S.C. 103(a) are summarized asfollows:
`
`1.
`2.
`
`Determining the scope and contents of the prior art.
`Ascertaining the differences betweenthe prior art and the claims atissue.
`
`JA00688
`GENV-00011446
`
`JA00688
`
`

`

`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 18 of 820 PageID #: 7504
`Case 1:22-cv-00252-MSG Document 181-2 Filed 01/03/24 Page 18 of 820 PagelD #: 7504
`
`Application/Control Number: 14/304,578
`Art Unit: 1616
`
`Page 3
`
`3.
`4.
`
`Resolving the level of ordinary skill in the pertinent art.
`Considering objective evidence present in the application indicating
`obviousness or nonobviousness.
`
`This application currently namesjoint inventors.
`
`In considering patentability of
`
`the claims under 35 U.S.C. 103(a), the examiner presumesth