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 without traverse of claims 2-15 and 20-25 with species election of a CMV promoter, SEQ ID NO:2, and AAV in the reply filed on March 20, 2026 is acknowledged.
Status of Claims
Claims 1-25 are currently pending in the instant application. Claims 16-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Accordingly, claims 1-15 and 20-25 are under examination on the merits in the instant application.
Information Disclosure Statement
The listing of references in paragraph 0187 of the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12-15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 12-15 recite that the “miR-142 target sequence” comprises ACACTA. It is noted that the sequence of ACACTA can pertain to only miR-142-3p, not miR-142-5p. Hence, the “miR-142” encompassing both isoforms, 3p and 5p, conflicts with the sequence requirement of ACACTA. For examination purpose, “miR-142” recited in the claims will be interpreted as miR-142-3p.
Claim 13 recites “wherein the miR-142 target sequence comprises ACACTA and 1-17 additional contiguous nucleotides of SEQ ID NO:5.” For discussion purpose, SEQ ID NO:5 is reproduced below, wherein the hexamer sequence recited in claim 13 is boxed.
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Now, the claim as written requires that the miR-142-3p target sequence should comprise “ACACTA” and up to “17 additional contiguous nucleotides of SEQ ID NO:5.” Hence, the 17 contiguous nucleotides fully encompass positions 7-23, which would contain “ACACTA”. As such, it is unclear whether the claimed target sequence comprises the hexamer and the 17-mer comprising the hexamer. Furthermore, it is unclear how “1” nucleotide can possibly form “contiguous nucleotides of SEQ ID NO:5.” That is, at least 2 nucleotides are necessarily to form “contiguous nucleotides”.
Claim Rejections - 35 USC § 112
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.
Claims 10-11 are 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.
Claims 10-11 recite that the AIMP2-DX2 gene-encoded sequence lacks SEQ ID NO:10 or 11, each of which is identified as exon 2 sequence AIMP2-DX2, wherein the term “AIMP2-DX2” is defined as “an exon 2-deleted AIMP2 variant” as expressly recited in claim 1. As such, claim 1 inherently as well as expressly requires that exon 2 should be absent in AIMP2-DX2-encoding sequence. Hence, the limitations recited in claims 10-11 requiring the absence of exon 2 protein sequence are inherently and expressly already recited in claim 1. Accordingly, claims 10-11 fail to further limit the subject matter of claim 1.
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.
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 1-15 and 20-25 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.
The factors to be considered when analyzing claims for compliance with the written description requirement include, but are not limited to: (A) actual reduction to practice; (B) sufficient relevant identifying characteristics (e.g., complete structure, partial structure, physical and/or chemical properties, structure/function correlation); (C) level of skill and knowledge in the art; and (D) predictability in the art. See MPEP §2163.
Each factor listed above is analyzed below.
(A) actual reduction to practice
The instant specification discloses an actual reduction to practice a method of treating wet AMD in wet AMD mouse models and a method of treating dry AMD mouse model comprising subretinally injecting an AAV2 vector comprising a CMV promoter operably linked to SEQ ID NO:1 encoding SEQ ID NO:2, wherein the vector does not comprise any miR-142 target sequence.
(B) sufficient relevant identifying characteristics
The instant specification at best identifies and adequately describes the required AMD treatment effect provided by an AAV2 vector comprising a CMV promoter operably linked to SEQ ID NO:1 encoding SEQ ID NO:2, wherein the vector comprises no miR-142 target site. That is, the specification fails to adequately describe the structure-function correlation for the genus of “AIMP2-DX2” recited without any SEQ ID NO (e.g., see claim 1) or “AIMP2-DX2 gene” encoding SEQ ID NOs:13-20 or 90% homologs of SEQ ID NOs:2 and 13-20 operably linked to a genus of various promoters (e.g., LTR, MT, UB6), wherein the genus of various sequences are required to provide the recited treatment function in a subject having wet AMD or dry AMD. Regarding the various amino acid sequences encompassed by and claimed in the instant claims, it is noted that, for instance, SEQ ID NO:20 is a 198 amino acid fragment of SEQ ID NO:2 that is 251 amino acids long, thereby sharing only about 78% with SEQ ID NO:2 encoded by the subretinally injected AAV2 construct in the working examples disclosed in the instant application. There is no adequate written description support in the instant specification that a vector encoding a polypeptide having only about 78% sequence identity with SEQ ID NO:2 would function in the same manner as that encoding SEQ ID NO:2 in wet and dry AMD animal models. Most importantly, the single nucleotide sequence of SEQ ID NO:1 encoding SEQ ID NO:2 is not a representative number of species for the “nucleotide sequence encoding an amino acid sequence that is at least 90% identical to SEQ ID NO:2, 13, 14, 15, 16, 17, 18, 19, or 20.” That is, SEQ ID NO:1 consisting of exons 1, 3, and 4 of AIMP2 contains no substituted, modified bases compared to the art-recognized AIMP2 transcript variant lacking exon 2. In other words, SEQ ID NO:1 is an unmodified, art-recognized transcript variant sequence of AIMP2 lacking exon 2, wherein the single unmodified nucleotide sequence of SEQ ID NO:1 is not a representative number of species within the broad genus of any “nucleotide sequence” encoding any one of SEQ ID NOs:2 and 13-20 and 90% homologs thereof because one of ordinary skill in the relevant art cannot extrapolate the required AMD treatment effect provided by a myriad of nucleotide sequence variants based on the experimental data pertaining to the single nucleotide sequence, SEQ ID NO:1. Simply put, there is no adequate written description support that any nucleotide sequence variant of SEQ ID NO:1 is able to encode the therapeutically effective polypeptide of AIMP2-DX2 for providing AMD treatment in a subject in need thereof.
In addition, the single viral vector, AAV2, and the single promoter, CMV, which are used to express SEQ ID NO:2 encoded by SEQ ID NO:1 in the retina of the wet and dry AMD animal models cannot represent the required structure-function correlation for the entire genus of a “recombinant vector” or “viral vector” comprising any “promoter” because the particular combination of the AAV2 vector and the CMV promoter used by the instant co-inventors for expressing SEQ ID NO:2 encoded by SEQ ID NO:1 was the most well-known, well-utilized combination for ocular disease gene therapy. See for instance Constable et al. (US 2018/0125948 A1). That is, the use of the well-known vector/promoter as disclosed in the instant specification is not sufficient to describe the therapeutic use of vectors that are not AAV2 comprising non-CMV promoter for treating an ocular disease, in particular, a retinal disease including AMD.
Regarding the inclusion of miR-142 target sequence comprising ACACTA in SEQ ID NO:5, which is complementary to thus binding to miR-142-3p, it is noted that the instant specification is completely silent regarding the structure-function correlation between a recombinant vector comprising the combination of a miR-142-3p-targeting sequence that is 3’ to the AIMP2-DX2-encoding sequence in providing AMD therapy in a subject in need thereof. As noted above in factor (A), the instant specification provides an actual reduction to practice the claimed AMD therapy only by subretinally injecting an AAV2 vector that does not comprise any miR-142 target sequence. The specification does not describe an AIMP2-DX2-encoding vector further comprising one or more of miR-142-3p-targeting sequences results in treatment of AMD in a subject in need thereof. There is simply no written description support for the claimed method that administers a vector encoding the combination of both AIMP2-DX2 and miR-142-3p-targeting sequences in the 5’ and 3’ direction.
(C) level of skill and knowledge in the art
The state of the prior art knowledge and skills pertaining to an ocular disease including AMD treatment using a viral vector encoding a therapeutic polypeptide was at best limited to subretinal injection of specific viral vector serotypes (e.g., AAV2) and specific promoters (e.g., CMV). For instance, Constable et al. (US 2018/0125948 A1) report that “AAV2 is the most characterized” and that “rAAV2 has been shown to be able to mediate long-term transgene expression in the eyes of many species of animals.” See paragraph 0212. Constable also teaches that the “recombinant virus, rAAV.sFlt-1, is a recombinant adeno-associated virus 2 (rAAV2) vector carrying the soluble VEGFR receptor 1 (VEGFR1) or sFLT-1 driven by the human cytomegalovirus (CMV) promoter.” See paragraph 0362. Moreover, Constable reports human study results for treating wet AMD comprising administering the rAAV.sFlt1 construct comprising “subretinal injection” of the pharmaceutical composition comprising rAAV.sFlt-1, which is an rAAV2 vector with the human CMV promoter. See Example 12. Coincidentally, the instant specification also describes subretinal injection of an AAV2 vector comprising a CMV promoter for AMD treatment thus fails to provide any more insight into using other vector species comprising other promoter species delivered via non-subretinal routes as broadly encompassed by the instant claims.
Regarding the state of the relevant art and skills for using miR-142-3p-targeting sequences included in gene therapy vector in providing AMD therapy, there is no relevant prior art. Interestingly, it was known in the art that the RPE/choroid tissues of dry AMD animal model significantly overexpress miR-142-3p by about 8-fold compared to the control such that miR-142-3p is the most differentially upregulated miRNA in the RPE/choroid tissues of dry AMD animal model. See Table 2 and Figure 4A of Huang et al. (IOVS, 2017, 58:1726-1735). Even more interestingly, it is reported in the post-filing art that miR-142-3p is significantly upregulated and overexpressed in the CNV lesion compared to healthy choroid in a laser-induced CNV mouse model, which is the same mouse model used by the instant co-inventors for wet AMD therapy experiments. See Figures 1 B-D of Roblain et al. (Aging, 2021, 13:12359-12377) who report that they “identified miR-142-3p as a specific CNV lesion microRNA, being upregulated both 5- and 7-days post laser-induction and displaying a correlation with uPA, a well-established CNV disease marker.” See page 12367. As such, it is a scientifically established fact that miR-142-3p is overexpressed in the affected ocular tissues of dry AMD and wet AMD. Now, it is extremely highly questionable as to how targeting the overexpressed miR-142-3p by the vector that includes one or more of miR-142-3p-targeting sequences can possibly help express the therapeutic polypeptide of SEQ ID NO:2 in the affected ocular tissues in AMD. That is, the inclusion of miR-142-3p-targeting sequences in an AIMP-DX2-encoding vector is postulated to inhibit or suppress AIMP2-DX2 expression in tissues/cells expressing miR-142-3p. See FIG. 2 of the instant application with the title: “Knockdown of DX2 expression by miR142-3pT”. Hence, one of ordinary skill in the relevant art would not whatsoever deem it scientifically feasible to overexpress the therapeutic polypeptide, AIMP-DX2, in AMD-affected ocular tissues by further including miR-142-3p-targeting sequences because the AMD-affected ocular tissues naturally overexpress miR-142-3p, which would in turn bind to the miR-142-3p-targeting sequences, thereby suppressing the expression of AIMP-DX2, the therapeutic polypeptide, in the AMD-affected ocular tissues, thereby consequently failing to treat AMD. Again, as noted in (A) and (B) factors analyzed above, the instant specification is completely silent regarding the AMD treatment effects provided by a vector that further comprises miR-142-3p targeting sequences, and the scientific data known in the prior art and consistently found in the post-filing art do strongly suggest that inclusion of miR-142-3p targeting sequences in an AIMP-DX2-encoding vector would not work to treat AMD for the reasons explained in detail above.
(D) predictability in the art
The level of predictability pertaining to treating wet or dry AMD comprising utilizing a non-subretinal injection route, a non-AAV2 vector, a non-CMV promoter, and inclusion of miR-142-3p-targeting sequences is deemed essentially nonexistent as of the filing date sought in the instant application in view of the teachings of Constable et al. (US 2018/0125948 A1), Huang et al. (IOVS, 2017, 58:1726-1735), and Roblain et al. (Aging, 2021, 13:12359-12377).
In view of the totality of factors (A)-(D) analyzed above, it is concluded that the instant specification is insufficient and deficient to adequately describe the entire genus of the claimed AMD treatment method as currently written. The specification thus fails to reasonably convey that the instant co-inventors completed and had possession of the entire genus of the AMD treatment method as of the filing date sought in the instant case.
Claims 1-15 and 20-25 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 treating wet AMD and dry AMD comprising subretinally injecting an AAV2 vector comprising a CMV promoter operably linked to SEQ ID NO:1 encoding SEQ ID NO:2, wherein the vector does not comprise any miR-142 target sequence, does not reasonably provide enablement for the entire scope. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’.” (Wands, 8 USPQ2d 1404). There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP §2164.
As extensively discussed in the written description rejection above, which is fully incorporated by reference herein thus will not be repeated, the instant specification’s disclosure including the working examples limited to subretinal injection of an AAV2 vector comprising SEQ ID NO:1 that is operably linked to a CMV promoter is not sufficient to support the entire breadth of the rejected claims, especially in light of the lack of relevant prior art knowledge/skills/predictability pertaining to the entire breadth of the rejected claims as evidenced by the teachings of Constable et al. (US 2018/0125948 A1), Huang et al. (IOVS, 2017, 58:1726-1735), and Roblain et al. (Aging, 2021, 13:12359-12377).
The instant specification does not provide any enabling disclosure and/or direction for using a non-subretinal injection route, a non-AAV2 vector, a non-CMV promoter, and inclusion of miR-142-3p-targeting sequences in order to practice the instantly claimed AMD treatment method. Hence, the factors (A)-(G) in combination do suggest that an undue amount of experimentation would be necessary for a person of ordinary skill in the art to practice the entire scope of the claimed AMD method. Accordingly, it is concluded that the instant specification does not provide an enabling disclosure commensurate in scope with the rejected claims.
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 1-15 and 20-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-22 of copending Application No. 16/819,998 in view of Lashkari (US 2020/0054745 A1).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims overlap in scope with the ‘998 claims drawn to a method of treating “retinal degeneration” comprising administering a vector encoding the AIMP2-DX2 gene and a miR-142 target sequence. It was known in the prior art that “retinal degeneration” encompasses AMD in wet and dry forms as evidenced by Lashkari. See paragraphs 0038-0039. Hence, one of ordinary skill in the art would have readily and reasonably envisioned that the method of the ‘998 claims fully encompasses the instantly claimed AMD treatment method in the manner that the conflicting claims overlap in scope with each other.
Claims 1-15 and 20-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-16, and 21-26 of copending Application No. 18/858,540.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the ‘540 claims drawn to a method of treating “a retinal degenerative disease” comprising administering an “adeno-associated virus” vector comprising a “CMV” promoter operably linked to the AIMP2-DX2 gene, further comprising an miR-142 target sequence comprising ACACTA, wherein the claimed retinal degenerative disease is defined to read on “age-related macular disease (AMD)” having the “dry” or “wet” form in the ‘540 specification. See paragraphs 0003 and 0007-0008.
Conclusion
No claim is allowed.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
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