DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group IV, now comprising amended claims 19 and 84 and newly added claims 85-92 (see below claim objections pertaining to numbering), drawn to a method of making scAAV vectors, in the reply filed on 04/10/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant’s assertion that claims 19 and 84-90 read on the elected group is acknowledged.
Applicant’s assertion that support for the new claims, 85-90, is found throughout the application and claims as originally filed, and that no new matter has been added is acknowledged. However, see the 112 rejection below regarding new matter.
Claims 1, 47, 52, 70, 71, 72 and 77-83 have been canceled by applicant.
Therefore, claims 19 and 84-90 are pending and are under examination at this time. However, see claim objections below regarding claim numbering.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
This application is a continuation of US application no. 17316769 with filing Date 05/11/2021, which is a continuation of US application no. 15568650 with filing date 10/23/2017, which is a national stage entry of PCT application no. PCT/US2016/027848 with filing date 04/15/2016, which claims domestic priority to US provisional application no. 62152602 with filing date 04/24/2015.
The examiner finds support for all claimed limitation in the earlier filed US provisional application; therefore, the examiner will consider the effective filing date to be 04/24/2015.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/28/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
The claims as instantly presented, list claim number 85 and 86 twice. In the interest of compact prosecution, the claims are renumbered as follows:
Misnumbered claim 85 (i.e., the second claim numbered 85) is renumbered to 87.
Misnumbered claim 86 (i.e., the second claim numbered 86) is renumbered to 88.
Misnumbered claim 87 is renumbered to 89.
Misnumbered claim is renumbered to 90.
Misnumbered claim 89 is renumbered to 91.
Misnumbered claim 90 is renumbered to 92.
Appropriate correction is required; however, for the purposes of this office action, claim numbering will be 19 and 84-92.
Claim 92 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 91. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
The examination of claim 91 satisfies the examination of claim 92.
Claim 19 is objected to because of the following informalities: the instant claim recites roman numeral “ii” twice. Appropriate correction is required.
Claim Interpretation
Claim 19 is interpreted as an isolated nucleic acid having only one ITR at a first terminus (i.e., at a 5’- terminus or a 3’- terminus) and then a hairpin sequence at a second terminus (i.e., the opposite 5’ – terminus or 3’ – terminus) without a second or any ITR following the hairpin sequence. Drawings depicting such configurations are found in FIG. 22A.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 19 and 84-92 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 19 was amended to recite a culturing step. However, the specification does not describe a method that comprises “culturing a host cell under conditions under which rAAV particles are produced.” While applicant asserts that support “is found throughout the application and claims as originally filed,” the applicant has not indicated to any particular section of the specification, and a review the specification indicates that the specification does not describe any method of producing a preparation of an rAAV that comprises culturing a host cell under conditions under which rAAV particles are produced.
Claims 19 and 84-92 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of producing a preparation of rAAV, the method comprising delivering to a host cell: an isolated nucleic acid having one wild-type or resolvable inverted terminal repeat at a first terminus and a promoter operably linked with a sequence encoding a hairpin-forming RNA at a second terminus, wherein the isolated nucleic acid is configured for forming a self-complementary AAV (scAAV) vector; ii) an AAV helper function vector encoding a Rep protein and a Cap protein; and iii) an AAV accessory function vector; and culturing the host cell under conditions under which rAAV particles are produced, does not reasonably provide enablement for a method of producing a preparation of rAAV, the method comprising delivering to a host cell: an isolated nucleic acid having one mutated, non-resolvable inverted terminal repeat at a first terminus and a promoter operably linked with a sequence encoding a hairpin-forming RNA at a second terminus, wherein the isolated nucleic acid is configured for forming a self-complementary AAV (scAAV) vector; ii) an AAV helper function vector encoding a Rep protein and a Cap protein; and iii) an AAV accessory function vector; and culturing the host cell under conditions under which rAAV particles are produced. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The scope is not enabled based on the specification’s own teachings and a determination of undue experimentation after an evaluation of the Wands Factors. The disclosure explicitly demonstrates that when an AAV vector genome having only a single mutated/non-resolvable terminal repeat, it is replication deficient and unable to be rescued, see FIG. 22A-22B and page 57 bottom half. Specifically, the specification teaches an AAV vector genome (pshDNA+ wtTR-) that comprises a mutated ITR at a first terminus and a hairpin sequence replacing the wild-type ITR at a second terminus, and that this AAV vector genome resulted in “no AAV genomes” being “rescued or replicated (FIG. 22B).”
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Furthermore, the applicant’s own drawings in FIG. 22A explicitly label the pshDNA+ wtTR- AAV vector genome as resulting in “no replication,” which is also shown in the gel image in FIG. 22B where no virus was rescued. However, when replacing the mutant ITR (mTR) with a hairpin at a first terminus and leaving the wild-type ITR intact at a second terminus, the specification teaches that “in the absence of the mTR sequence, scAAV genomes were efficiently rescued from all constructs containing shRNA cassettes,” allowing for vector production and in vivo transduction. Thus, the specification asserts “the importance of the wild-type terminal repeat for AAV replication,” during the production of a preparation of rAAV, page 57 bottom half. An evaluation of the Wands Factors reveals that the scope of claim 19 (and thus all dependent claim thereof) is not enabled:
The breath of the claims: the claims recite a method of producing a preparation of rAAV comprising delivering to a host cell an isolated nucleic acid “having one inverted terminal repeat at a first terminus.” Because the claims recite broadly “inverted terminal repeat” without limiting the sequence to a wild-type, functional, or resolvable ITR, the scope encompasses AAV vector genomes where the single ITR is mutated and non-functional/non-resolvable (e.g., a delta-trs sequence or a wtTR- configuration).
The nature of the invention: the invention relates to a specialized field of molecular virology and recombinant gene therapy vector engineering. Specifically, it involves modifying AAV vector genomes to optimize rAAV production by overcoming the rate-limiting step for efficient transduction by rAAVs (i.e., second-stand synthesis of the AAV single stranded DNA genome).
State of the prior art: Hastie and Samulski (Hum Gene Ther.;26(5):257–265, 2015 Mar 23) provide an excellent review of the state of the art at the time of filing. Hastie and Samulski teach that the prior art had established “the necessity of AAV ITRs for replication,” see introduction and pg. 258 second column. Hastie and Samulski further teach while the industry had evolved to engineer modified, asymmetrical, or self-complementary vector genomes, a functional origin of replication (i.e., a resolvable ITR) must remain present in the vector genome, see pg. 258 end of column one and top of column two, pg. 260 first column, and pg. 261 column 1.
The level of ordinary skill in the art: a person having ordinary skill in the art would typically hold a PhD in molecular biology, virology, or an equivalent biological sciences field, and have multiple years of laboratory experiences specializing in recombinant viral vector cloning, plasmid construction, and transfection and viral packaging protocols.
The level of predictability in the art: the level of predictability is low, especially when manipulating the ITRs, and that the biology of the single-stranded AAV genome is sensitive to structural changes, see Hastie and Samulski pg. 258 and first column pg 259.
The amount of direction provided by the inventor: the specification provided ample technical direction for practicing producing rAAV architectures employing functional flanking terminal repeats such as self-complementary vector genomes the comprise a wild-type ITR and a mutated ITR, and even viral genome architectures employing only a single functional ITR and a hairpin replacing the mutant ITR of a scAAV. However, the specification provided zero direction or technical guidance on how a person having ordinary skill in the art could successfully generate an rAAV preparation if the solitary ITR located at a first terminus is a non-resolvable mutant.
The existence of working examples: the specification contains no working examples showing the successful generation of an rAAV preparation using an isolated nucleic acid where the single terminal repeat is non-resolvable . In fact, the applicant’s own data provides a clear example of inoperability for this configuration, see discussion above pertaining to the pshDNA+ wtTR- AAV vector genome.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: the production of a preparation of an rAAV having a single non-resolvable ITR would require a person having ordinary skill on the art to engage in undue and excessive quantity of experimentation to discover or engineer non-conical, alternative replication mechanism that are unmentioned in the disclosure.
In conclusion, the applicant’s own specification and the virology principles discussed by Hastie and Samulski demonstrate that preparations of rAAV vector genomes having a single mutated (i.e., non-resolvable) ITR are not able to be produced without undue experimentation. All dependent claims inherit the scope of enablement of independent claim 19.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 87 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Independent claim 19 already recites a promoter operably linked to a sequence encoding a hairpin-forming RNA. Therefore, the limitation, “wherein the sequence encoding the hairpin-forming RNA is operably linked with a promoter,” is already required by claim 19 and does not further restrict the scope of the claim 19. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 19 and 84-92 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-6 of U.S. Patent No. 11046955B2 in view of Qu G. and Wright JF. (EP2277996B1, herein “Qu”).
Although the claims at issue are not identical, they are not patentably distinct from each other. Both claim sets are drawn to self-complimentary adeno -associated virus (scAAV) vectors comprising the same core structural configurations. Claim 19 of the instant application is broader than the patent claims because it does not restrict the construct to a configuration other than the ITR at a first terminus and hair-pin loop under a promoter at a second terminus, for example. The scAAV vectors of each claim set are represent patentably indistinct, obvious variations of one another.
The instant claims differ from the patented claims primarily in that the instant claims are directed to a method of producing a preparation of recombinant AAV (rAAV), whereas the patented claims are directed to the composition of the scAAV vector itself.
US11046955B2 does not explicitly claim a method of preparing an rAAV comprising delivering to a host cell i) the obvious iteration of the scAAV vector, ii) an AAV helper function vector encoding a Rep protein and a Cap protein, and iii) an AAV accessory function vector; and culturing the host cell under conditions under which rAAV particles are produced. Furthermore, US11046955B2 does not claim that the method results in at least 80% of the rAAVs in the preparation comprise a non-truncated genome and at least 90% of the rAAVs in the preparation comprise a non-truncated genome.
Qu teaches the conventional methodology for manufacturing rAAV vectors using both an AAV helper function vector and an AAV accessory function vector in a host cell system (see “AAV Helper Functions” [0062-0066] and AAV Accessory Functions [0067-0071]). Qu further teaches the downstream “Purification of rAAV Virions” to ensure the preparations are high purity and substantially free of empty capsids (see [0072-0085]). Qu further teaches culturing the host cell under standard conditions which functional rAAV particles are produced, see [0061].
Regarding the dependent claim limitations requiring the preparations to contain at least 80% or 90% non-truncated genomes, these purity metrics are an inherent physical characteristic resulting directly from the specific scAAV designs disclosed in US11046955B2 and the instant application. An underpinning technological features of the patented invention is that placing the hairpin-forming RNA at the distal terminus (i.e., not proximate to the 3’ WT ITR) prevents polymerase stalling and yields significantly more intact, non-truncated genomes upon viral replication (see column 31 lines 35-40 of US11046955B2). Furthermore, US11046955B2 explicitly recites that the scAAV viral genome is capable of producing recombinant adeno-associated viral particles, making it inherent that these intact scAAV vectors are successfully packaged with ITRs.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) to employ the conventional manufacturing method of Qu, utilizing AAV helper function and an AAV accessory function vectors, and optimized host cell culture, to produce preparations of rAAV as claimed in US11046955B2. A PHOSITA would have been motivated because the methods of Qu produce high quality (i.e., preparations free from empty capsids) rAAV preparations and commercially viable levels. A PHOSITA would have had a reasonable expectation of success because Qu already demonstrated producing rAAV preparations using this exact triple-vector configuration.
Claims 19 and 84-92 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12054715B2 in view of Qu G. and Wright JF. (EP2277996B1, herein “Qu”).
US12054715B2 claims the exact scAAV vector structure as a composition of matter. The patent claims and instant claims differ only in that the instant claims are directed to a method of producing rAAV particles utilizing the patented the scAAV vector composition.
The teaching of Qu are incorporated herein by reference to the NSDP rejection above.
It would have been obvious for a PHOSITA to employ the routine production method of Qu, comprising delivering the patented scAAV vector compositions to a host cell along with a standard AAV helper function vector and an AAV accessory function vectors, and culturing the host cell under conditions under which rAAV particles are produced, to manufacture the preparations claimed in the instant application.
A PHOSITA would have been motivated and had a reasonable expectation of success for the same reasons as detailed above in the NSDP rejection above.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached M-F 7:30am - 6:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/COREY LANE BRETZ/Patent Examiner, 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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