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 .
Claim Status
Applicant’s preliminary amendments received 13JUN2023 are acknowledged.
Claims 32-74 have been canceled.
Claims 6, 8-10, 15, 28-29 have been amended.
Claims 1-31 (i.e., Claims 1 and 30-31 are independent) are pending in the instant application.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/US2022/011894, filed 11JAN2022, which claims the benefit of
US Provisional Patent Application No. 63/296694, filed 05JAN2022,
US Provisional Patent Application No. 63/284248, filed 30NOV2021,
US Provisional Patent Application No. 63/277298, filed 09NOV2021,
US Provisional Patent Application No. 63/227054, filed 29JUL2021,US Provisional Patent Application No. 63/192262, filed 24MAY2021,
US Provisional Patent Application No. 63/160380, filed 12MAR2021,
US Provisional Patent Application No. 63/155029, filed 01MAR2021, and
US Provisional Patent Application No. 63/135932, filed 11JAN2021. Applicant’s claim for the benefit of prior-filed application is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 05SEP2023 (3x) and 13DEC2024 is/are acknowledged and the references cited therein have been considered.
Specification
The disclosure is objected to because of the following informalities:
The INCORPORATION-BY-REFERENCE OF MATERIAL section is missing from the specification see p 3, lines 4-6 of the specification filed 30JUN2023 showing an example of material incorporated by reference.
The BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S) section is missing from the specification.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see p 8, 72, 77, 80, 109, 112-114, and 127 of the specification). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The lengthy specification has not been checked to the extent necessary to determine the presence of and to catalog all possible minor errors. Applicant’s assistance and cooperation in finding and correcting any errors of which the applicant may become aware of in the specification is appreciated.
Claim Objections
Claims 1-7, 11, and 22 are objected to because of the following informalities:
Claims 1-4 and 6 should be updated to “anti-N3pGlu” for purposes of consistency.
Claim 5 contains a typographical error, wherein a space should be inserted between “<” and “24.1” and further contains the abbreviation of “CL” which while permissible, the first recitation of the term should include the full recitation followed by the abbreviation in parentheses.
Claim 7 should be updated to include what the “-E” notates with regards to amyloid-related imaging abnormalities.
Claim 11 contains the acronyms “iADRs” or “CDR-SB” in section (a) of claim 11. While acronyms are permissible as shorthand in the claims, the first recitation of the term should include the full recitation followed by the acronym in parentheses as done in sections (c) or (e) of claim 11.
Claim 11 section (d) does not contain a unit following “at least 3….”
Claim 22 contains the gene “APOE4” in line 1 of claim 22. While acronyms are permissible as shorthand in the claims, the first recitation of the term should include the full recitation followed by the acronym in parentheses.
Appropriate correction is required.
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 8-10, 25, and 28-29 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.
The term “temporarily” in claims 8 and 9 is a relative term which renders the claim indefinite. The term “temporarily” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In this instance, donanemab may be temporarily discontinued if it meets the criteria of Table A; and may be exemplarily restarted after temporary discontinuation due to ARIA-E and complete resolution of symptoms and MRI findings within 16 weeks after the temporary discontinuation (p 84-85). The rejection would be obviated by replacing temporarily with a precise time limit for discontinuation e.g., donanemab is withheld for up to 16 weeks wherein there is complete resolution of ARIA-E symptoms and MRI findings and permanently discontinued after 16 weeks wherein there is incomplete resolution of ARIA-E symptoms and MRI findings.
Claim 8 recites the limitation "symptoms consistent with ARIA occur" which is dependent on claim 7. In this instance, claim 7 does not reference ARIA[-E] symptoms, rather ARIA-E findings by MRI and therefore there is insufficient antecedent basis for this limitation in the claim. Claims 9-10 are also rejected since they depend from claim 8 but do not remedy this deficiency.
Claim 25 recites the limitation "level of Aß plaques in the brain of the subject is sustained at normal levels" which is dependent on claim 20. Claim 20 dependent on claim 1, recites an outcome wherein donanemab does not reduce the subject’s hippocampal volume during the course of administration and does not discuss the level of Aß plaque. Therefore, there is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, claim 25 will be examined on the merits as being dependent on claim 24 for the remainder of the office action.
Claims 28-29 recite the limitation "wherein the subject has an increase in tau level of less than…" which are dependent upon claim 23 which recites the desired outcome of a normal level of Aß plaques for at least 52 weeks after completing administration of the second dose. Therefore, because there is no mention of tau levels in claim 23, there is insufficient antecedent basis for this limitation in these 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 1-2, 4, 6-7, 11, 17, 19, 21-22, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,312,763 B2, herein referred to as “’763” in view of Kwan, et al., (Dementia and Geriatric Cognitive Disorders, 25DEC2020, 49, 334-348), herein referred to as “Kwan” and as evidenced by Perneczky, et al., (The Am J of Geriatric Psychiatry, 2006, 14, 139-144), herein referred to as “Perneczky.”
The issued claims of the ‘763 patent recite:
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However, they do not claim: administration of one or more second doses of 1400 mg (e.g., 20 mg/kg for a 70 kg subject); or the subject has a baseline MMSE score of 20-28 prior to administration of the antibody; or wherein the subject has at least one APOE4 allele.
Nevertheless, Kwan teaches the outcomes of several anti-Aß antibody clinical trials as well as recommendations for future clinical trials. Specifically, ARIA-E is one of the adverse events observed in anti-Aß monotherapies and it has been shown that APO E4/E4 or E4/E3 carriers are generally at higher risk of ARIA (Discussion section). In an effort to reduce adverse effects, slow titration up to the target dose (i.e., effective dose) reduces ARIA-E incidence in both APOE4 carriers and noncarriers (Gantenerumab section). Kwan further teaches that future clinical trials should be conducted in patients in the early stages of the progression model of AD development (i.e., as evidenced by Perneczky, a MMSE score of 21-28 falls in the mild cognitive impairment-normal or being tau negative in the frontal lobe brain region), but Aß-positive subjects (Discussion section). Currently in the progression model for AD, the biomarkers begin with amyloid buildup, followed by metabolic decline, CSF tau accumulation, and eventually brain volume reduction, and thus it is necessary to administer the anti-Aß antibody therapy in the early stages of the disease to be more effective. Furthermore, Kwan teaches future studies should consider optimal dosage to reduce adverse events, such as ARIA-E, but get to the target dosage prior to the development of moderate cognitive impairment (Gantenerumab and Discussion Section).
It would have been obvious to artisans to modify the issued methods of reducing Aß deposits in a human brain comprising a 3 to 60 mg/kg dose or 700 mg of an anti-Aß antibody comprising SEQ ID NOs: 25/26 (i.e., 100% query match to SEQ ID NOs: 1/2 of the instant application, respectively, see OA.APPENDIX) every four weeks for up to 6 months (i.e., 24 weeks) as claimed by the ‘763 patent to include a titrated dose scheme, as taught by Kwan. This is because Kwan teaches that ARIA-E is a concerning adverse event for anti-Aß antibody therapies and by utilizing a titration dosing scheme, ARIA-E adverse events are reduced in both APOE4 carriers and non-carriers and because Kwan further teaches that choosing the appropriate population is important so that the antibody is administered early enough to be beneficial (i.e., mild cognitive impairment, negative tau PET scan in the frontal lobe). One would have been motivated to do so, given the direction by the ‘763 patent that a broad range of doses effectively reduced Aß deposits. There would have been a reasonable expectation of success, given the knowledge that by modifying the therapeutically effective dosing taught by the ‘763 patent by a titrated dose that falls within the range of those taught in ‘763 (i.e., second doses of 1400 mg (e.g., 20 mg/kg for a 70 kg subject)), which provides a method resulting in fewer adverse effects, as taught by Kwan.
Claim 1-2, 4, 6-7, 11, 17, 19, 21-23, 26-27, 30-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 8,679,498 B2, (included in IDS) herein referred to as “’498” and in view of WO 2018/005282 (Eli Lilly and Company, et al., 04JAN2018, included in IDS), herein referred to as “282” and Kwan, et al., (Dementia and Geriatric Cognitive Disorders, 25DEC2020, 49, 334-348), herein referred to as “Kwan” and as evidenced by Perneczky, et al., (The Am J of Geriatric Psychiatry, 2006, 14, 139-144), herein referred to as “Perneczky.”
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The issued claims of ‘498 recite:
However, they do not claim: administration of three 700 mg doses (e.g., 10 mg/kg for a 70 kg subject) every four weeks, and then four weeks after administration of the third dose administration of one or more second doses of 1400 mg (e.g., 20 mg/kg for a 70 kg subject); or the subject has a baseline MMSE score of 20-28 prior to administration of the antibody; or wherein the subject has at least one APOE4 allele.
Nevertheless, ‘282 teach the treatment, prevention, or slowed progression of a disease characterized by Aß deposits in the brain of a patient comprising administering an induction dose of 10 to 60 mg/kg once every month (i.e., 4 weeks) of antibody comprising SEQ ID NOs: 25/26 (i.e., 100% query match for SEQ ID NOs: 14/15 of the ‘498 patent and SEQ ID NOs: 1/2 of the instant application, see OA.APPENDIX) for a period of 6 months or less, wherein the Aß deposits in the brain are reduced by 35-100% within 6 months, or reduced by 50% within 6 months or wherein the reduction is maintained for a period of 2-10 years (see entire document, specifically see claims 1, 4, 5, 14-16, 19, 26-28).
Additionally, Kwan teaches the outcomes of several anti-Aß antibody clinical trials as well as recommendations for future clinical trials. Specifically, ARIA-E is one of the adverse events observed in anti-Aß monotherapies and it has been shown that APO E4/E4 or E4/E3 carriers are generally at higher risk of ARIA (Discussion section). In an effort to reduce adverse effects, slow titration up to the target dose (i.e., effective dose) reduces ARIA-E incidence in both APOE4 carriers and noncarriers (Gantenerumab section). Kwan further teaches that future clinical trials should be conducted in patients in the early stages of the progression model of AD development (i.e., as evidenced by Perneczky, a MMSE score of 21-28 falls in the mild cognitive impairment-normal or being tau negative in the frontal lobe brain region), but Aß-positive subjects (Discussion section). Currently in the progression model for AD, the biomarkers begin with amyloid buildup, followed by metabolic decline, CSF tau accumulation, and eventually brain volume reduction, and thus it is necessary to administer the anti-Aß antibody therapy in the early stages of the disease to be more effective. Furthermore, Kwan teaches future studies should consider optimal dosage to reduce adverse events, such as ARIA-E, but get to the target dosage prior to the development of moderate cognitive impairment (Gantenerumab and Discussion Section).
It would have been obvious to artisans to modify the issued methods of treating AD comprising administering the engineered antibody of SEQ ID NOs: 14/15 (i.e., 100% query match to SEQ ID NOs: 1/2 of the instant application) as claimed by the ‘498 patent by a method which reduces Aß deposits in a human brain comprising administering a titrated dose scheme comprising a 10 mg/kg and a 20 mg/kg dose (i.e., 700 mg and 1400 mg dose for a 70 kg subject), as taught by ‘282 and Kwan. This is because ‘282 teaches a wide therapeutically effective dose for reducing Aß deposits (i.e., treating AD) and Kwan teaches that ARIA-E is a concerning adverse event for anti-Aß antibody therapies and by utilizing a titration dosing scheme, ARIA-E adverse events are reduced in both APOE4 carriers and non-carriers and because Kwan further teaches that choosing the appropriate population is important so that the antibody is administered early enough to be beneficial (i.e., mild cognitive impairment, negative tau PET scan in the frontal lobe). One would have been motivated to do so, given the direction by the ‘498 patent that the antibody of SEQ ID NOs: 14/15 effectively treats a disease related to Aß deposits such as AD. There would have been a reasonable expectation of success, given the knowledge that by modifying the administration of the anti-Aß antibody taught by the ‘498 patent by a titrated dose that falls within the range of those taught in ‘’282 (i.e., second doses of 1400 mg (e.g., 20 mg/kg for a 70 kg subject)), which provides a method resulting in fewer adverse effects, as taught by Kwan.
Provisional NSDP
Claims 1, 6, 11-15, 19, 21-22, and 30-31 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-17, 21-22, 24-27, 31-47, and 54-55 of co-pending Application No. 18/550214; herein referred to as the “reference application.” Although the claims at issue are not identical, they are not patentably distinct from each other because the method of treating, preventing, or retarding the progression of AD in a specific human patient population, comprising administering a therapeutically effective amount of an anti-Aß antibody (I.e., donanemab) of the reference application is an obvious variation of the method of reducing Aß plaques (i.e., treating AD) or slowing progression of AD (i.e., retarding the progression of AD) comprising administering a specific dosing regimen of a specific anti-N3pGlu Aß antibody (donanemab) of the instant application. Specifically, the anti-Aß antibody of the reference application is further limited to donanemab using a dosing regimen that is an obvious variation of claims 1 and 30-31 of the instant application.
The co-pending claims of the reference application recite: A method of treating, preventing, or retarding the progression of Alzheimer's Disease (AD) in a human subject who has been determined to have i) slow progressing AD cognitive decline or ii) slow progressing AD cognitive decline and/or one or two alleles of APOE e4, comprising administering a therapeutically effective amount of an anti-Aß antibody (i.e., claim 8). The method of claim 8, wherein the human subject has been determined to have slow progressing AD cognitive decline by one [or] more of ADAS-Cog, iADL, CDR-SB, MMSE, APOE-4 genotyping, tau levels, P-tau levels, and/or iADRs (i.e., claim 14). The method of claim 14, wherein the human subject has been determined to have slow progressing AD cognitive decline by MMSE, wherein the human subject has been determined to have MMSE of above 27 (i.e., claims 24-25). The method of claim 8, wherein the Aß antibody comprises an anti-N3pG[lu] Aß antibody, wherein the anti-N3pG[lu] antibody comprises a LCVR and HCVR comprising amino acid sequences as set forth in SEQ ID NOs: 1 and 2, respectively (i.e., claims 37-38). The method of claim 8, wherein said step of administering comprises: (i) administering to the human subject one or more first doses of about 100-700 mg of an anti-N3pG[lu] antibody, wherein each first dose is administered once about every four weeks; and (ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of > 700-1400 mg of the anti-N3pG[lu] antibody, wherein each second dose is administered once about every four weeks, wherein the human subject is administered the first dose, once to three times before administering the second dose, and wherein the human subject is administered first doses of about 700 mg or wherein the human subject is administered one or more second doses of about 1400 mg or wherein the anti-N3pGlu antibody is administered to the human subject for a duration of up to 72 weeks (i.e., claims 39-41, and claim 43-44, respectively).
In this instance, because the method of treating, preventing, or retarding the progression of AD in a subject of the reference application includes the same steps as the instant application (i.e., administering (i) three doses of a first dose of 700 mg of an anti-N3pGlu Aß antibody and about four weeks after administration of the third first dose (ii) one or more doses of a second dose of 1400 mg of an anti-N3pGlu Aß antibody), and because the antibody of the reference application and instant application are the same (i.e., VL/VH sequences set forth in SEQ ID NOs: 1 and 2 of the reference application are 100% query match to SEQ ID NOs: 1 and 2 of the instant application) (see OA.APPENDIX), there is no clear difference in the scope between the methods of the instant and reference applications. In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the methods claimed in the instant application and those of the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5, 11-15, 17, 21-22, 24, and 30-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-16, 19-22, 32-33, 38-39, 56, 69-70, and 73-74 of co-pending Application No. 18/549803; herein referred to as the “’803 reference application.” Although the claims at issue are not identical, they are not patentably distinct from each other because the method of treating or preventing a disease characterized by Aß deposits in the brain of a human subject of the ‘803 reference application is an obvious variation of the method of reducing Aß plaques in the brain of a human subject or methods of slowing disease progression in a human AD subject of the instant application.
The co-pending claims of the ‘835 reference application recite:
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The specific SEQ ID NOs for the anti-Aß antibodies of claim 1 and in the dosing regimen of dependent claim 21 of the ‘803 reference application are not specifically claimed; however, the anti-Aß antibody is considered generic. In order to determine the scope of the method of treatment and the structure of donanemab, the specification is consulted. On p 18-21 of the ‘803 reference application specification, the anti-Aß antibodies can include LC of SEQ ID NO: 3 and VH of SEQ ID NO: 2 (i.e., 100% query match to SEQ ID NOs: 1 and 2 of the instant application, see OA.APPENDIX) or donanemab. Therefore, there is no clear difference in the scope between the methods of the instant and reference applications. In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the methods claimed in the instant application and those of the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 13-14, and 30-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 and 37 of co-pending Application No. 18/727835; herein referred to as the “’835 reference application.” Although the claims at issue are not identical, they are not patentably distinct from each other because the method of identifying a patient having or suspected of having AD as a candidate patient for receiving an AD therapy, the method comprising analyzing a tau-PET scan from a brain region and identifying the patient as a candidate if the tau-PET SUVr ranges from about 1.05 to 1.45, the method further comprising administering AD therapy to the patient wherein the therapy is donanemab or a method of treating a patient, comprising analyzing tau-PET SUVr and administering an AD therapy to the patient of the ‘835 reference application, is an obvious variation to a method of reducing Aß plaques (i.e., treating) comprising administering donanemab using a specific dosing regimen of the instant application.
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The co-pending claims of the ‘835 reference application recite:
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The dosing regimen and the specific SEQ ID NOs for the anti-N3pGlu Aß antibodies of claim 19 of the ‘835 reference application are not specifically claimed; however, the step of administering an AD therapy to a patient in claim 16 or in independent claims 17-18 of the ‘835 reference application, or wherein the AD therapy is donanemab in claim 19 is considered a generic method of administration of an AD therapeutic (i.e., anti-N3pGlu Aß antibody, specifically donanemab). In order to determine the scope of the method of treatment and the structure of donanemab, the specification is consulted. In ¶0043-0046 of the ‘835 reference application, treating AD using a dosing regimen of three doses of 700 mg every four weeks of donanemab and then one or more doses of 1400 mg every four weeks of donanemab until brain amyloid plaque is cleared, wherein the donanemab has a LC/HC of SEQ ID NOs: 1/2, respectively (i.e., 100% QM to VL/VH of SEQ ID NOs: 1/2, respectively of the instant application, see OA.APPENDIX). Therefore, there is no clear difference in the scope between the methods of the instant and reference applications. In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the methods claimed in the instant application and those of the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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.
Claim 1-2, 4, 6-7, 11, 17, 19, 20-23, 26-27, 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/005282 (Eli Lilly and Company, et al., 04JAN2018, included in IDS), herein referred to as “282” and Kwan, et al., (Dementia and Geriatric Cognitive Disorders, 25DEC2020, 49, 334-348), herein referred to as “Kwan” and as evidenced by Perneczky, et al., (The Am J of Geriatric Psychiatry, 2006, 14, 139-144), herein referred to as “Perneczky.”
‘282 teach the treatment, prevention, or slowed progression of a disease characterized by Aß deposits in the brain of a patient comprising administering an induction dose of 10 to 60 mg/kg once every month (i.e., 4 weeks) of antibody comprising SEQ ID NOs: 25/26 (i.e., 100% query match for SEQ ID NOs: 1/2 of the instant application, see OA.APPENDIX) for a period of 6 months or less, wherein the Aß deposits in the brain are reduced by 35-100% within 6 months, or reduced by 50% within 6 months and wherein the reduction is maintained for a period of 2-10 years, and a(see entire document, specifically see claims 1, 4, 5, 14-16, 19, 26-28).
However, they do not teach: administration of one or more second doses of 1400 mg (e.g., 20 mg/kg for a 70 kg subject); or the subject has a baseline MMSE score of 20-28 prior to administration of the antibody; or wherein the subject has at least one APOE4 allele.
Nevertheless, Kwan teaches the outcomes of several anti-Aß antibody clinical trials as well as recommendations for future clinical trials. Specifically, ARIA-E is one of the adverse events observed in anti-Aß monotherapies and it has been shown that APO E4/E4 or E4/E3 carriers are generally at higher risk of ARIA (Discussion section). In an effort to reduce adverse effects, slow titration up to the target dose (i.e., effective dose) reduces ARIA-E incidence in both APOE4 carriers and noncarriers (Gantenerumab section). Kwan further teaches that future clinical trials should be conducted in patients in the early stages of the progression model of AD development (i.e., as evidenced by Perneczky, a MMSE score of 21-28 falls in the mild cognitive impairment-normal or being tau negative in the frontal lobe brain region), but Aß-positive subjects (Discussion section). Currently in the progression model for AD, the biomarkers begin with amyloid buildup, followed by metabolic decline, CSF tau accumulation, and eventually brain volume reduction, and thus it is necessary to administer the anti-Aß antibody therapy in the early stages of the disease to be more effective. Furthermore, Kwan teaches future studies should consider optimal dosage to reduce adverse events, such as ARIA-E, but get to the target dosage prior to the development of moderate cognitive impairment (Gantenerumab and Discussion Section).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating, preventing, or slowing the cognitive decline comprising administering one or more induction doses of 10-60 mg/kg (i.e., 700 to 4200 mg per 70 kg subject) of an anti-N3pGlu Aß antibody comprising SEQ ID NOs: 25/26 (i.e., 100% query match for SEQ ID NOs: 1/2 of the instant application) for a period of 6 months or less as disclosed by ‘282 to include a titrated dose scheme, as taught by Kwan. This is because Kwan teaches that ARIA-E is a concerning adverse event for anti-Aß antibody therapies and by utilizing a titration dosing scheme, ARIA-E adverse events are reduced in both APOE4 carriers and non-carriers and because Kwan further teaches that choosing the appropriate population is important so that the antibody is administered early enough to be beneficial (i.e., mild cognitive impairment, negative tau PET scan in the frontal lobe). One would have been motivated to do so, given the teachings of ‘282 that the therapeutically effective dose of the anti-N3pGlu antibody set forth in SEQ ID NOs: 25/26 is broad. There would have been a reasonable expectation of success, given the knowledge that by modifying the therapeutically effective dosing taught by ‘282 to using a titrated dose that falls within the range of those taught in ‘763 (i.e., second doses of 1400 mg (e.g., 20 mg/kg for a 70 kg subject)), would lead to a method resulting in fewer adverse effects, as taught by Kwan.
Although ‘282 and Kwan are silent with regard to the administration of the antibody does not reduce the subjects hippocampal volume during the course of the administration in claim 20, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) and MPEP §2112.01). Therefore, in the absence of evidence to the contrary, the method of administration taught by ‘282 and Kwan would have the claimed properties recited in claim 20.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Allowable Subject Matter
Claims 7 and 18 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 7 and 18 are objected to.
Claims 1-6, 8-17, and 19-31 are not allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641