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 .
DETAILED ACTION
Claim Status
Claims 1-2, 18-26 and 29-32 are pending. Claims 3, 17 and 28 have been canceled. Claims 1, 19 and 30-32 have been amended. Claims 1-2, 18-26 and 31-32 are being examined in this application. In the response to the restriction requirement, Applicants elected Group I; SEQ ID NO: 3, wherein the peptide is acetylated, and wherein the peptide is oxidized; donepezil (the acetylcholinesterase inhibitor); intravenous administration; and Alzheimer’s disease. Claims 29-30 are withdrawn as being drawn to a nonelected invention.
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.
This rejection has been modified.
Claims 1-2, 18-26 and 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over Bridon et al. (US 2018/0265549) in view of AmbioPharm (downloaded from URL:<https://www.ambiopharm.com/faq/advantage-of-capping-n-and-c-termini/>, May 14, 2019) and Tan et al. (Aust J Gen Pract. 2018 Sep;47(9):586-592).
With respect to claims 1, 23-24 and 32, Bridon et al. teach a method of treatment of Alzheimer’s disease comprising administering SEQ ID NO: 59 (claim 25; paras [0121] and [0123]), which corresponds to instantly claimed SEQ ID NO: 1.
Bridon et al. also teach that the peptide is administered through a systemic route (paras [0007], [0013]; passim).
Bridon et al. further teach that the peptide is linear or cyclic (paras [0170], [0187], [0189]).
Bridon et al. do not teach that the N-terminal amino acid is acetylated, the C-terminal amino acid is amidated, or both.
Bridon et al. also do not teach that treatment with donezepil is contraindicated in said subject, or said subject is resistant to donezepil.
AmbioPharm teaches that “[A]cetylation or capping of the N-terminus will make a peptide appear more like native protein. It also helps to minimize amino peptidase degradation of the peptide. Amidation of the C terminus also helps to stabilize the peptide from carboxypeptidase degradation” (page 1).
Tan et al. teach the current approaches to the pharmacological treatment of Alzheimer’s disease (title; abstract; passim).
Tan et al. also teach that “[T]he Guidelines recommend that for people taking an AChEI and/or memantine for longer than 12 months, a trial of discontinuation is considered if cognition and/or function has deteriorated significantly during the previous six months, if there was no benefit observed at any time during therapy, or if the person has severe or advanced dementia in which there is little hope of a meaningful benefit to continued therapy. Other reasons for discontinuation include poor tolerance despite dose reduction or medication switching, comorbidities or non-adherence that make continued use unacceptably risky or futile” (page 589, left column, 2nd para).
Tan et al. further teach that currently available AChEIs include donepezil, galantamine and rivastigmine.
It would have been obvious to one of ordinary skill in the art to make the peptide of Bridon et al. wherein the N-terminal amino acid is acetylated and the C-terminal amino acid is amidated in order to make the peptide appear more like native protein.
The skilled artisan would have reasonably expected to minimize amino peptidase degradation and to stabilize the peptide from carboxypeptidase degradation.
With respect to the limitation “wherein treatment with donepezil is contraindicated in said subject, or said subject is resistant to donepezil”, one of ordinary skill in the art would have been motivated to administer the treatment obvious over the references to subjects wherein treatment with donepezil is contraindicated, or to subjects resistant to donepezil because Tan et al. teach that in certain subpopulation of patients with Alzheimer’s disease discontinuation of AChEI is warranted.
With respect to claims 2 and 18-22, Bridon et al. teach that the peptide is SEQ ID NO: 2 (claim 3), which corresponds to instantly claimed SEQ ID NOs: 2-3.
With respect to claim 25, as discussed above, the peptide of Bridon et al. is used for the treatment of Alzheimer’s disease (which is characterized by increased tau protein level, tau protein aggregation, and tau protein hyperphosphorylation), thus, it would inherently reduce tau protein level, tau protein aggregation, and tau protein hyperphosphorylation. Therefore, the skilled artisan would have reasonably expected the acetylated and amidated peptide obvious over the references to reduce tau protein level, tau protein aggregation, and tau protein hyperphosphorylation.
With respect to claim 26, Bridon et al. teach intravenous administration (paras [0011], [0119]-[0120]).
With respect to claim 31, Bridon et al. teach administering the peptide and a pharmaceutically acceptable excipient (claims 13 and 23; paras [0117]-[0118]).
Response to Arguments
Applicant’s arguments filed on 8/21/2026 have been fully considered but they are not persuasive.
Applicant argues that “[t]he claims are now in accordance with the examples, and they require the presence of NX210 or NX218 (i.e. the reduced or oxidized form of SEQ ID NO: 3, respectively) in combination with donepezil”.
Applicant also argues that “[B]ridon only refers to patients in a generic way (see, e.g., paragraphs [0007] and [0121]) and clearly does not disclose or suggest the specific patients of the present claims. In addition, neither the AmbioPharm or Tam references disclose or suggest the elements of the present claims missing in Bridon and thus cannot make up for the deficiencies in Bridon as shown above. With regard to the cited AmbioPharm reference, this reference at most describes possible chemical modifications for peptides and does not provide any disclosure or suggestion of Applicant's claimed method wherein treatment is targeted directly to patients wherein treatment with donepezil is contraindicated or the subject is resistant to donepezil. Similarly, Tan also does not disclose or suggest the elements missing in Bridon. At most, Tan relates generally to the current approaches to the pharmacological treatment of Alzheimer's disease including an acetylcholinesterase inhibitor (AChEI) such as donepezil, galantamine, and rivastigmine”.
Applicant further argues that “[T]an clearly does not disclose or anywhere suggest there are any alternatives to the discontinuation of treatment with an AChEI, much less one that is directed to patients as in the claimed method wherein the specific peptides set forth in the claims are used for treatment where donepezil is contraindicated or the subject is resistant to donepezil. Instead, the other treatments disclosed in Tan are memantine, antipsychotics, and citalopram (Table 2). It is thus clear that neither AmbioPharm or Tan or disclose or suggest the elements missing in Bridon and thus cannot make up for the deficiencies in Bridon as shown above. Applicant thus submits that the Examiner's rejection on the basis of the combination of Bridon, AmbioPharm and Tan are thus respectfully traversed and should be withdrawn on this basis alone. Even further, as referred to above, Applicant's claimed invention has achieved surprising and unexpected results as shown in the examples in Applicant's specification. More specifically, Example 4 of the present application discloses that the efficacy response to acetylcholine esterase inhibitors such as Donepezil (DPZ) (standard of care) is unpredictable, and with a loss of efficacy seen over time. However it was surprisingly demonstrated by the claimed inventors that the combination ofNX210 or ofNX218 (claimed peptides) at a subactive dose with DPZ at a subactive dose, significantly and fully restores both:
- Ab25-35-induced spatial short-term working memory deficits (Table 8 and Figure 4), showing a synergistic therapeutic effect between the drugs on tauopathies-related cognitive impairments; and
- Ab25-35-induced long-term memory deficits (STL and EL, Tables 9-10 and
Figure 5). This result confirms a synergistic beneficial effect of the combination of
NX210 or NX218 with an inhibitor of acetylcholine esterase (here DPZ) on
tauopathies-related cognitive impairments.
In addition, Example 6 shows the long-term effects of these peptide treatments: and it is clearly demonstrated that following DPZ resistance after 4 weeks of treatment, NX218 treatment (Group 5) completely rescued memory loss for up to 17 weeks (between 53% and 80% of alternation depending on the time and dose of NX peptide administered)”.
Applicant’s arguments are not persuasive because the claim, as amended, are NOT commensurate in scope with the claimed invention. The claims do NOT require specific doses of NX210 or NX218 in combination with donezepril.
Claim 1 recites “wherein treatment with donepezil is contraindicated in said subject, or said subject is resistant to donepezil”. Nowhere in this limitation, the administration of NX210 or NX218 is in combination with donezepril.
Furthermore, the MPEP 716.02(e) states that “[e]vidence of unexpected results must compare the claimed invention with the closest prior art”.
In the instant case, to rebut a prima facie case of obviousness, Applicant should compare the instantly claimed peptide with the peptide of Bridon et al.
With respect to Applicant’s arguments regarding Bridon et al. not disclosing or suggesting the specific patients instantly claimed, it is noted that Bridon et al. teach that “[T]hese medicaments or compositions may, in particular, be used in the treatment of Alzheimer's disease” (paras [0121] and [0123]). Alzheimer's disease is tauopathy, thus reading on the instantly claimed method of treating tauopathy.
Moreover, the MPEP 2123 states that “[D]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have "relatively acceptable dimensional stability" and "some degree of flexibility," but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since "Gurley asserted no discovery beyond what was known in the art." Id. at 554, 31 USPQ2d at 1132.). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004)”.
In the instant case, contrary to Applicant’s arguments, Bridon et al. clearly teach treating tauopathy (paras [0121] and [0123]).
With respect to Applicant’s arguments regarding AmbioPharm, it is noted that AmbioPharm teaches that “[A]cetylation or capping of the N-terminus will make a peptide appear more like native protein. It also helps to minimize amino peptidase degradation of the peptide. Amidation of the C terminus also helps to stabilize the peptide from carboxypeptidase degradation” (page 1).
Therefore, one of ordinary skills in the art would have been motivated to acetylate the N-terminal amino acid and to amidate the C-terminal amino acid of the peptide of Bridon et al. so to make the peptide appear more like native protein.
The skilled artisan would have reasonably expected to minimize amino peptidase degradation and to stabilize the peptide from carboxypeptidase degradation.
With respect to Applicant’s arguments regarding Tan et al., it is noted that Tan et al. is drawn to the current approaches to the pharmacological treatment of Alzheimer’s disease (title; abstract; passim), which is the same disease treated by Bridon et al.
Tan et al. specifically teach that “[T]he Guidelines recommend that for people taking an AChEI and/or memantine for longer than 12 months, a trial of discontinuation is considered if cognition and/or function has deteriorated significantly during the previous six months, if there was no benefit observed at any time during therapy, or if the person has severe or advanced dementia in which there is little hope of a meaningful benefit to continued therapy. Other reasons for discontinuation include poor tolerance despite dose reduction or medication switching, comorbidities or non-adherence that make continued use unacceptably risky or futile” (page 589, left column, 2nd para).
Therefore, since Tan et al. teach that in certain subpopulation of patients with Alzheimer’s disease discontinuation of AChEI is warranted, the skilled artisan would have been motivated to administer the treatment obvious over the references to subjects wherein treatment with donepezil (which is an Acetylcholinesterase Inhibitor) is contraindicated, or to subjects resistant to donepezil.
For these reasons, the rejection is maintained.
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.
This rejection has been modified.
Claims 1-2, 18-26 and 31-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-34 of copending Application No. 18/576443 in view of Hanson et al. (Cell Rep. 2020 Jan 14;30(2):381-396.e4) and Tan et al. (Aust J Gen Pract. 2018 Sep;47(9):586-592).
With respect to claims 1 and 23-24, ‘443 teaches a method of treating a subject in need thereof to enhance or restore GluN2A-NMDAr-mediated glutamatergic neurotransmission, the method comprising administering to the subject a therapeutic amount of a peptide and a pharmaceutically acceptable vehicle or excipient, wherein said peptide has the following amino acid sequence X1-W-S-Al-W-S-A2-C-S-A3-A4-C-G-X2 in which :- Al, A2, A3 and A4 consists of amino acid sequences consisting of 1 to 5 amino acids, - X1 and X2 consists of amino acid sequences consisting of 1 to 6 amino acids; or X1 and X2 are absent; it being possible for the N-terminal amino acid to be acetylated, for the C-terminal amino acid to be amidated, or the N-terminal amino acid to be acetylated and the C- terminal amino acid to be amidated (claim 15).
‘443 also teaches that the peptide is administered through a systemic route (see specification at page 18, line 22). Please note that it is proper to turn to and rely on the disclosure of a patent application to ascertain what constitutes an obvious modification. This position is supported by the courts. See In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970).
‘443 further teaches that the peptide is linear or cyclic (claim 25).
‘443 does not teach that the disease is Alzheimer’s disease (i.e. a tauopathy).
‘443 also does not teach that treatment with donepezil is contraindicated in said subject, or said subject is resistant to onepezil.
Hanson et al. teach that GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer’s Disease Models (title; passim).
Tan et al. teach the current approaches to the pharmacological treatment of Alzheimer’s disease (title; abstract; passim).
Tan et al. also teach that “[T]he Guidelines recommend that for people taking an AChEI and/or memantine for longer than 12 months, a trial of discontinuation is considered if cognition and/or function has deteriorated significantly during the previous six months, if there was no benefit observed at any time during therapy, or if the person has severe or advanced dementia in which there is little hope of a meaningful benefit to continued therapy. Other reasons for discontinuation include poor tolerance despite dose reduction or medication switching, comorbidities or non-adherence that make continued use unacceptably risky or futile” (page 589, left column, 2nd para).
Tan et al. further teach that currently available AChEIs include donepezil, galantamine and rivastigmine.
It would have been obvious to one of ordinary skill in the art to use the method of ‘443 to treat Alzheimer’s disease because Hanson et al. teach that GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Alzheimer’s Disease Models.
With respect to the limitation “wherein treatment with donepezil is contraindicated in said subject, or said subject is resistant to donepezil”, one of ordinary skill in the art would have been motivated to administer the treatment obvious over the references to subjects wherein treatment with donepezil is contraindicated, or to subjects resistant to donepezil because Tan et al. teach that in certain subpopulation of patients with Alzheimer’s disease discontinuation of AChEI is warranted.
With respect to claim 2, ‘443 teaches that the peptide is SEQ ID NO: 2 (claim 21).
With respect to claim 18, ‘443 teaches that A1 is chosen from G, V, S, P and A, A2 is chosen from G, V, S, P and A, A3 is chosen from R, A and V, and/or A4 is chosen from S, T, P and A (claim 22).
With respect to claims 19, 21-22 and 32, ‘443 teaches that the peptide is of a sequence selected from the group consisting of sequences SEQ ID NO: 3- 63 (claim 24).
With respect to claim 20, ‘443 teaches that A1 and A2 are independently chosen from G and S, and/or A3-A4 is chosen from R-S or V-S or V-T or R-T (claim 23).
With respect to claim 25, the MPEP 2112.01 states that “'Products of identical chemical composition cannot have mutually exclusive properties.’ A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
In the instant case, the peptide of ‘443 is the same peptide instantly claimed; thus, it would inherently have the same properties (i.e. inducing the reduction or disruption of tau aggregation, reducing tau protein, and reducing the level of phosphorylated tau protein).
With respect to claim 26, ‘443 teach intravenous administration (page 19, line 6).
With respect to claim 31, ‘443 teaches administering the peptide and a pharmaceutically acceptable excipient (claim 15).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments filed on 8/21/2026 have been fully considered but they are not persuasive.
Applicant argues that “[t]he present claims are now directed to a method of treating a tauopathy in a subject in need thereof, wherein, in said subject, treatment with DPZ is contraindicated, or wherein said subject is resistant to DPZ, and it is clear that the claims of the '443 App. do not claim such a limitation. Moreover, this limitation is not disclosed or suggested in the other references cited by the Examiner. For example, Hanson at most teaches that GluN2A NMDA Receptor enhancement improves brain oscillations, synchrony, and cognitive functions in Alzheimer's Disease Model, but does not disclose or suggest treating a subject for whom treatment with acetylcholinesterase inhibitors is contraindicated, or who is resistant to acetylcholinesterase inhibitors. In view of Hanson, the skilled artisan would not reasonably consider that GluN2A NMDA Receptor enhancement would have any related effect to acetylcholinesterase inhibitors. It results that Hanson cannot be added to the '443 App. claims to make up for the deficiencies as shown above. Further, Tan also does not disclose or suggest the missing elements from the '443 app. as shown above and instead only teaches that acetylcholinesterase inhibitors are used for the treatment of Alzheimer's disease, and not in cases wherein treatment with an acetylcholinesterase inhibitor such as donepezil is contraindicated or where the patient is resistant to such treatment. Tan thus also cannot make up for the deficiencies in the '443 App. claims as shown above”.
Applicant’s arguments are not persuasive.
Applicant’s arguments with respect to Tan et al. have been addressed above.
With respect to Applicant’s arguments regarding Hanson et al., it is noted that Hanson et al. teach that GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer’s Disease Models.
On the other hand, ‘443 teaches enhancing or restoring GluN2A-NMDAr-mediated glutamatergic neurotransmission.
Therefore, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to use the method of ‘443 to treat Alzheimer’s disease.
For these reasons, the rejection is maintained.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SERGIO COFFA whose telephone number is (571)270-3022. The examiner can normally be reached M-F: 6AM-4PM.
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/SERGIO COFFA Ph.D./
Primary Examiner
Art Unit 1658
/SERGIO COFFA/Primary Examiner, Art Unit 1658
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