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 .
Status of Application/Amendments/Claims/RCE under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e) was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicants’ submission filed on 4/17/2026 has been considered.
Claims 1, 17, 18 are amended. Claim 6 is canceled. Claims 1-5, 7-12 and 16-23 are pending and are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Applicant’s claim for the benefit of a prior-filed application EP19382447.1 and 371 of PCT/EP2020/065018 published 5/31/2019 and 5/29/2020, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 5/31/2019.
Claim Rejections - 35 USC§ 112, Scope of Enablement
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 1-5, 7-12 and 16-23 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 treating neuroinflammation, neurodegeneration and/or cognitive decline or a disease or condition associated therewith in a subject in need thereof, does not reasonably provide enablement for a method for preventing such disease states as presently claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the claimed method for the prevention of neuroinflammation, neurodegeneration and/or cognitive decline or a disease or condition associated therewith in a subject in need thereof. This rejection is supported by the disclosure of Folch et al. "The implication of the brain insulin receptor in late onset Alzheimer’s disease dementia." Pharmaceuticals 11.1 (2018): 11 (hereinafter Folch).
The factors listed below have been considered in the analysis of enablement regarding methods for wound healing comprising the administration of ANY antidepressant:
(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.
The breadth of claims read on a method for preventing neuroinflammation, neurodegeneration and/or cognitive decline or a disease or condition associated therewith in a subject in need thereof. The term “preventing” embraces a range of possible patient outcomes from total to partial prevention of neuroinflammation, neurodegeneration and/or cognitive decline or ANY disease or condition associated therewith, which is considered extraordinarily broad.
The instant specification does not provide sufficient examples, protocols and outcomes relating to an enabling disclosure for methods to completely preventing neuroinflammation, neurodegeneration and/or cognitive decline. The specification does describe SAMP8 mice which were administered AAV9-Ins with furin cleavage sites and showed decrease expression of pro-inflammatory genes Nfkb, Il1b and Il6 and an increase in expression of the astrocyte markers Gfap and S100b. The specification further describes effects in db/db mice which after administration of AAV9-Ins with furin cleavage sites showed decrease expression of the pro-inflammatory genes Nfkb, Il1b and Il6 and an increase in expression of the astrocyte markers Gfap and S100b. Although applicant has showed a decrease expression of the pro-inflammatory genes and an increase in expression of the astrocyte markers upon administration of a vector encoding an insulin protein, this is not sufficient evidence to show that all diseases or conditions associated with neuroinflammation, neurodegeneration and/or cognitive decline can be completely prevented.
The examiners search of the prior art finds no supportive evidence for the complete prevention of neuroinflammation, neurodegeneration and/or cognitive decline. For example, Folch describes the role of insulin and AB interactions on reduced neuronal IR signaling (Fig 1 and 2). Folch describes the molecular basis of insulin receptor modulation and relationship to Tau phosphorylation (section 4). However, Folch is silent to the mechanisms of how insulin expression could result in the complete prevention of neuroinflammation, neurodegeneration and/or cognitive decline. It is emphasized that the claim to prevention has a higher requirement for an enabling disclosure than a claim to a treatment.
An amendment to change the word prevention to treatment would be remedial. Should the applicant disagree with the above enablement analysis, the applicant is invited to submit prior art to support the statement of complete prevention of neuroinflammation, neurodegeneration and/or cognitive decline. Accordingly, since both the instant specification and prior art are silent on methods for the complete prevention of cerebral hemorrhaging using MSCs, the scope of prevention is not enabled.
Maintained Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 7-8, 11-12 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Ishii et al. US 2008/0248099, published 10/9/2008 (hereinafter Ishii, reference of record) in view of Tang et al. US 2004/0142884, published 4/22/2004 (hereinafter Tang, reference of record). This rejection is maintained for the same reasons as set forth in the Office Action mailed on 1/22/2026. A reply to applicants’ traversal is found below.
Claims 1 and 7-8: Ishii describes a method for treating diseases of the nervous system by administering a viral vector encoding a nucleotide sequence encoding insulin and expression into the central nervous system (CNS) (Ishii, para 29, 39 and claim 17). Ishii found that insulin broadly acts as a neurotrophic factor and can treat a variety of diseases of the CNS (Ishii, para 33).
Claims 11 and 23: Ishii describes treating neurodegenerative diseases like Alzheimer’s (Ishii, claim 1).
Claim 12: Ishii describes delivery into the intra- cerebrospinal fluid (Ishii, para 45).
Ishii does not expressly describe the encoded insulin comprising a furin cleavage site or a nucleotide sequence encoding insulin consisting of the amino acid sequence that has at least 80% sequence identity to SEQ ID NO: 42.
Claim 1: Tang describes a method for engineering non-beta like cells to secrete insulin in a glucose-responsive manner for treating diabetes (Tang, para 12, 102). Tang describes the expression of a mutated pre-proinsulin cDNA that includes a furin cleavage site at the B-C and C-A junctions (Tang, Fig 1 and example 1). Tang describes how incorporating furin cleavage sites into the proinsulin sequence allows the non-beta cells which typically have furin but lack the specific convertases found in pancreatic beta cells to accurately and efficiently cleave the proinsulin precursor to yield biologically active insulin (Tang, para 15, 22, and example 1).
Claim 1: Tang discloses a nucleic acid sequence with 100% sequence similarity to instant SEQ ID NO: 42 (sequence search results shown below). Notably, the furin cleavage site is highlighted in red.
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Sequence alignment for SEQ ID NO: 333 from Tang against instant SEQ ID NO: 42
It would have been prima facie obvious to one of ordinary skill in the art to substitute the specific human insulin cDNA sequence comprising a furin cleavage site as disclosed by Tang for the recombinant cDNA described by Ishii. It would have been a matter of simply substituting one known human insulin cDNA sequence for another to obtain predictable results given that Ishii expressly describes the use of recombinant insulin from humans, but falls short of providing the specific sequence comprising a furin cleavage site as described in claims 1 and 6 (Ishii, para 37). One would have been motivated to make this substitution given that incorporating a furin cleavage sites into the proinsulin sequence allows the non-beta cells which typically have furin but lack the specific convertases found in pancreatic beta cells to accurately and efficiently cleave the proinsulin precursor to yield biologically active insulin (Tang, para 15, 22, and example 1). One would have a reasonable expectation of success given that the substitution of one known cDNA sequence for another in a viral vector is routine in the art and that there are known advantages of incorporating a furin cleavage site into proinsulin precursors to improve therapeutic outcomes as demonstrated by the disclosure of Tang. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 1, 7-8, 11-12 and 23 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the rejection by arguing against the Office interpretation of the preamble, wherein the preamble is limiting and is a statement of the intentional purpose for which the method must be performed.
It is noted that the previous claim interpretation statement has been withdrawn and a new 35 USC§ 112, Scope of Enablement rejection has been applied with respect to applicants claims of prevention. Furthermore, it is noted that the disclosure of Ishii considers methods for treating and preventing (Ishii, claim 23).
Applicant points to amended claim 1 which incorporates elements of canceled claim 6 and specifies the amino acid sequence of the expressed insulin protein comprising a furin cleavage site. Applicant argues that Ishii describes the administration of purified mature insulin protein to the brains of diabetic rats via osmotic minipumps and does not teach constructs encoding an insulin protein comprising a furin cleavage site. Applicant acknowledges that Ishii discloses administering a vector encoding the insulin gene into the CNS (Ishii, para 29).
These arguments have been fully considered, but were not found persuasive since patents are relevant as prior art for all they contain. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, see MPEP 2123. Although it may be true that Ishii teaches the administration of purified mature insulin protein to the brains of diabetic rats via osmotic minipumps, as Applicant has acknowledged, Ishii also discloses methods towards administering a vector encoding the insulin gene into the CNS which reads on the claimed invention (Ishii, para 29).
Applicant further argues that Tang does not cure the deficiencies of Ishii since the methods are only shown in HepG2 cells and not in cells of the central nervous system. Applicant argues that Tang is directed towards treating diabetes and therefore one of ordinary skill would not be motivated to combine the teachings with Ishii towards the treatment of neuroinflammation. Applicant points to the specification and examples which describe SAMP8 mice which were administered AAV9-Ins with furin cleavage sites and showed decrease expression of pro-inflammatory genes Nfkb, Il1b and Il6 and an increase in expression of the astrocyte markers Gfap and S100b. The specification further describes effects in db/db mice which after administration of AAV9-Ins with furin cleavage sites showed decrease expression of the pro-inflammatory genes Nfkb, Il1b and Il6 and an increase in expression of the astrocyte markers Gfap and S100b. Applicant argues that these are unexpected results.
These arguments have been fully considered, but were not found persuasive since Tang describes how incorporating furin cleavage sites into the proinsulin sequence allows the non-beta cells which typically have furin but lack the specific convertases found in pancreatic beta cells to accurately and efficiently cleave the proinsulin precursor to yield biologically active insulin (Tang, para 15, 22, and example 1). Importantly, HepG2 are non-beta cells and therefore one would have been motivated to make this substitution given that incorporating a furin cleavage sites into the proinsulin sequence allows the non-beta cells which typically have furin but lack the specific convertases found in pancreatic beta cells to accurately and efficiently cleave the proinsulin precursor to yield biologically active insulin (Tang, para 15, 22, and example 1). With respect to the purported unexpected results, one would have a reasonable expectation of success given that the substitution of one known cDNA sequence for another in a viral vector is routine in the art and that there are known advantages of incorporating a furin cleavage site into proinsulin precursors to improve therapeutic outcomes as demonstrated by the disclosure of Tang.
Claims 1-5, 7-12 and 16-23 are rejected under 35 U.S.C. 103 as being unpatentable over Ishii (supra) in view of Tang (supra) as applied to claims 1, 7-8, 11-12 and 23 above in further view of Dominguez et al. US 2018/0265893, published 9/20/2018 (hereinafter Dominguez, reference of record). This rejection is maintained for the same reasons as set forth in the Office Action mailed on 1/22/2026. A reply to applicants’ traversal is found below.
A description of Ishii and Tang can be found above. Neither Ishii nor Tang describes the use of a ubiquitous CAG promoter, the specific expression vector limitations or the use of a target sequence in the gene construct of a microRNA expressed in the liver and heart tissue in which transgene expression is intended to be prevented.
Claim 1: Dominguez describes gene expression constructs comprising a nucleotide sequence encoding an insulin-like growth factor (IGF) and methods for treating type 1 diabetes (Dominguez, abstract and para 5, 12-22).
Claims 2-3 and 17: Dominguez describes the expression of the nucleotide sequence encoding IGF under the control of the ubiquitous CAG promoter (Dominguez, para 23).
Claims 4-5 and 18: Dominguez describes expression of IGF operably liked to a ubiquitous promoter having a target sequence of a microRNA expressed in the liver and heart tissue in which IGF expression is intended to be prevented (Dominguez, para 12, 40, 41). Dominguez provides embodiments to target sequences of microRNA which share 100% sequence similarity to instant SEQ ID Nos: 7 and 8, respectively (Dominguez, para 71).
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Sequence search results, instant SEQ ID No: 7 as compared to SEQ ID No: 8 from Dominguez
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Sequence search results, instant SEQ ID No: 8 as compared to SEQ ID No: 15 from Dominguez
Claims 7-10, 16 and 19-22: Dominguez describes the use of a viral expression vector including AAV serotype 6 and pharmaceutically acceptable ingredients (Dominguez, para 88-92 and 118). Dominguez provides preferred embodiments to AAV serotype 1 and 9 vectors (Dominguez, para 161).
It would have been prima facie obvious to one of ordinary skill in the art to modify the insulin expressing vector of Ishii in view of Tang to include a ubiquitous promoter having a target sequence of a microRNA expressed in the liver and heart tissue in which insulin expression is intended to be prevented as described by Dominguez. It would have been a matter of combining prior art elements according to known methods to yield predictable results since all expression vector elements were known in the art. Furthermore, the disclosure of Ishii describes how insulin broadly acts as a neurotrophic factor and can treat a variety of diseases of the CNS (Ishii, para 33). Thus, one would have been motivated to make this combination in order to minimize off-target insulin expression in the heart and liver tissue and improve therapeutic efficacy by specifically administering and targeting the CNS (Dominguez, para 15-23). One would have a reasonable expectation of success given that both insulin and IGF are closely related hormones and in the same technical field. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the rejection by arguing that Dominguez does not cure the deficiencies of Ishii and Tang because Dominguez teaches the administration of IGF-1 protein and not insulin protein, which is an entirely different therapeutic agent.
These arguments have been fully considered, but were not found persuasive since Tang fully discloses a nucleic acid sequence with 100% sequence similarity to instant SEQ ID NO: 42 which includes a furin cleavage site. Dominguez is introduced as prior art to show the ubiquitous promoter having a target sequence of a microRNA expressed in the liver and heart tissue in which insulin expression is intended to be prevented. One would have been motivated to make this combination in order to minimize off-target insulin expression in the heart and liver tissue and improve therapeutic efficacy by specifically administering and targeting the CNS (Dominguez, para 15-23).
Conclusion
No claims allowed.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634
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