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 .
Response to Amendments
Applicant's amendments filed 7/15/2525 to claims 1, 3-5, 7, 9 and 12 have been entered. Claim 2 has been canceled. Claims 1 and 3-13 remain pending and are being considered on their merits. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and applicant’s comments.
Claim Rejections - 35 USC § 103
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 and 3-13 remain rejected under 35 U.S.C. 103 as being unpatentable over Cella et al (WO 2017147509 A1) in view of Melchior et al (2010, ASN Neuro, 2:3, AN20100010, DOI: 10.1042/AN20100010; 5/4/2022 IDS), and as evidenced by National Library of Medicine (NCBI) (2006, TMEM176B protein [Homo sapiens] GenBank: AAH91471.1, 14-SEP-2006).
Regarding claims 1, 3-6, 9-10 and 12, Cella teaches methods of treating or alleviating symptoms associated with a neurodegenerative disease including Alzheimer's disease, comprising administering to the subject an adeno-associated viral vector comprising a polynucleotide encoding human TREM2 to increase the expression of TREM2 (see abstract, paragraphs 28, 32, 67, 69, & 85-86, and claims 12-21). Regarding claim 11, Cella teaches adeno-associated viral vector is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9 or AAV10 (see paragraphs 67 and 69). Regarding claim 12-13, Cella teaches that the vector comprising the TREM2 construct may be in a host cell that is an animal cell, that is deposited in the subject (see paragraphs 66-67 and 80-81).
Cella does not teach that the treatment also includes administering a polynucleotide encoding human TMEM176B to increase the expression of TMEM176B (reads on administering TMEM176B).
Regarding claims 1, 4-6, 9-10 and 12, Melchior teaches that both TREM2 and TMEM176B have dual rules in including Alzheimer's disease, that they are both highly expressed in plaque-associated microglia, and are associated with amyloid plaque deposition (see title, abstract and Figure 3). Regarding claims 1, 6-10 and 12, Melchior teaches transfection of TMEM176B into both microglial and macrophage cell lines in in vitro assays established that TMEM176B increased apoptosis of the plaque-associated cells, and therefore play a role in clearing plaques associated with Alzheimer's disease (see abstract and page 166). Regarding claims 1, 4-6, 9-10 and 12, Melchior teaches that while TREM2 was most prominently induced in cells on the outer zones of the plaques, TMEM176B expression was most prominent in cells in the inner zone of plaques (page col 1 on page167). Therefore, regarding claims 4-5, Melchior further establishes that Cella’s Alzheimer's disease subjects have both a higher level of amyloid-beta or an aggregation level of amyloid-beta, and more dysfunctional phagocytosis activity of glial cells.
Regarding claim 3, NCBI is an inherency reference cited solely for teaching SEQ ID NO: 1 is identical to the sequence of human TMEM176B protein (see attached reference and alignment below).
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It would have been obvious to combine Cella and Melchior to also include polynucleotide encoding human TMEM176B to also increase the expression of human TMEM176B (reads on administering TMEM176B) in Cella’s Alzheimer's disease treatment. A person of ordinary skill in the art would have had a reasonable expectation of success in including a polynucleotide encoding human TMEM176B to also increase the expression of human TMEM176B in Cella’s Alzheimer's disease treatment, because Melchior establishes that TMEM176B can also be expressed in animal cells and that it pays a dual role with Cella’s TREM2. The skilled artisan would have been motivated to include polynucleotide encoding human TMEM176B to also increase the expression of human TMEM176B in Cella’s Alzheimer's disease treatment because Melchior teaches that both TREM2 and TMEM176B have dual rules in including Alzheimer's disease, that they are both highly expressed in plaque-associated microglia, and are associated with amyloid plaque deposition, and that while TREM2 was most prominently induced in cells on the outer zones of the plaques, TMEM176B expression was most prominent in cells in the inner zone of plaques, and therefore it could be useful to use them together. Additionally, Melchior teaches transfection of TMEM176B into both microglial and macrophage cell lines in in vitro assays established that TMEM176B increased apoptosis of the plaque-associated cells, and therefore play a role in clearing plaques associated with Alzheimer's disease, which further provides motivation.
Regarding claims 1, 9 and 12, with regards to the “a therapeutically effective amount” as the references teach the treatment is a beneficial therapeutic treatment, their teachings read on this limitation .
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Response to Arguments
Applicant's arguments filed 7/15/2525 have been fully considered but they are not persuasive.
Applicant highlights that Cella does not teach administering TMEM176B as claimed. However, the rejection is not over Cella alone, but rather over Cella in view of Melchior. For the reasons stated in the above rejection, it is the secondary reference Melchior that provides both teachings and motivation to include a polynucleotide encoding human TMEM176B to also increase the expression of human TMEM176B (reads on administering TMEM176B) in Cella’s TREM2 Alzheimer's disease treatment. Therefore this argument directed at Cella alone is not persuasive.
Applicant alleges that Melchior teaches that TMEM176B is inferior to TREM2, and concludes that Melchior therefore does not provide motivation to administer TMEM176B. Applicant also notes that Melchior suggests that future studies should be done to further elucidate the roles of TMEM176B. However, as stated in the above rejection, Melchior specifically teaches that both TREM2 and TMEM176B have dual rules in Alzheimer's disease, that they are both highly expressed in plaque-associated microglia, and are associated with amyloid plaque deposition. Indeed, even the title of the Melchior publication states this as the paper is titled “Dual Induction of TREM2 and Tolerance-Related Transcript, Tmem176b, in Amyloid Transgenic Mice: Implications for Vaccine-Based Therapies for Alzheimer’s Disease”. Therefore, although Melchior discusses that it is known that overexpression of TREM2 has been established to decrease amyloid pathology in Alzheimer's disease, the Melchior publication further identifies TMEM176B, and the conclusions in Melchior is that both TREM2 and TMEM176B have dual roles in this protection. Therefore, although Melchior teaches TREM2 has been studied more extensively and has better defined roles in protection from Alzheimer’s disease systems than TMEM176B, does not take away from Melchior’s specific teaching that both TREM2 and TMEM176B have dual rules in Alzheimer's disease and that both should be considered therapeutic targets. Therefore this argument is not persuasive.
Applicant alleges that Melchior does not provide motivation to include TMEM176B treatment, alleging that Melchior teaches that TMEM176B overexpression could be toxic to some cells. To support this conclusion, applicant points to one assay where Melchior’s teaching that TMEM176B overexpression could be toxic to some cell lines. However, Melchior preformed other assays wherein brain cells overexpressed TMEM176B since Melchior wasn’t able to use other stable cell lines, thereby indicating that TMEM176B can be overexpressed in brain cells. Therefore, this teaching that Melchior was unsuccessful in using TMEM176B to create some stable cell lines for in vitro assays does not take away from Melchior specific teaching that it is beneficially expressed in brain cells. Additionally, regarding the other references in Melchior to TMEM176B inducing apoptosis in other cells, as stated in the rejection, Melchior established that TMEM176B increased apoptosis of the plaque-associated cells, and therefore play a role in clearing plaques associated with Alzheimer's disease. Indeed, Melchior further highlights this beneficial role in their conclusion in column 2 on page 168 wherein Melchior specifically highlights TMEM176B may promote death of neurotoxic macrophages. Therefore this argument is not persuasive.
Conclusion
No claims are free of the art. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/S.A.M/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653