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/Restriction
Applicant’s election without traverse of the following species in the reply filed on 04/30/2026 is acknowledged:
Alzheimer’s
Detecting
APLP1
Retromer Dysfunction
Amount
A composition comprising a nucleic acid or transgene encoding VPS35
Nucleic acid
Promoter
Small molecules
Adeno-associated virus (AAV)
AAV9.
Claims 8, 13, 14, 15, 16, 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/30/2026.
Regarding the following groups of species from the Restriction 02/02/2026, upon reevaluation the following species have been rejoined:
B) Measuring has been rejoined with detecting
C) Tau and CHL1 have been rejoined with APLP1
D) Endosomal trafficking dysfunction has been rejoined with retromer dysfunction
E) Level has been rejoined with amount
F) i) a pharmacological chaperone which increases VPS35 and ii) a viral vector comprising a nucleic acid or transgene encoding the VPS35, have been rejoined with a composition comprising a nucleic acid or transgene encoding VPS35
G) Nucleic acid has been joined with transgene
H) Enhancer has been rejoined with promoter
Claim Status
Claims 4, 6, 8, 13, 14, 15, 16, 17 are withdrawn. Claims 2, 7, 12, 19, 22 are canceled. Claims 1, 3, 5, 6, 8, 9-11, 13-18, 20-21, 23-25 are pending. Claims 1, 3,9-11, 18, 20, 21, and 23-25 are herein examined.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 10/26/2023 are in compliance with the provisions of 37 CFR 1.97. Sources Vagnozzi et al., Cataldo et al., and NIH Grant #5R03AG064628-02 submitted on IDSs dated 10/26/2023 were not placed in the application contents and have been lined through.
Accordingly, the information disclosure is being considered by the examiner, except where lined through.
Claim Objections
Claim 3 is objected to because of the following informalities: it recites both CHLI and CHL1 but the specification teaches CHL1. It also recites APLPI, but the specification teaches APLP1. For the purposes of claim interpretation CHLI will be interpreted as CHL1 and APLPI will be interpreted as APLP1. Appropriate correction is required.
Claim 5 is objected to because of the following informalities: it recites CHLI and APLPI but the specification teaches CHL1 and APLP1, respectively. For the purposes of claim interpretation CHLI and APLPI will be interpreted as CHL1 and APLP1, respectively. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 5 is 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.
Claim 5 contains the trademark/trade name SIMOA assay. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a biomarker assay and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 112(a)
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, 3, 5-11, 18, 20, and 21-25 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 treating Alzheimer’s, does not reasonably provide enablement for preventing or curing it. 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.
MPEP § 2164.01(a) states that 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.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims:
The claims recite a method of treating, preventing, and/or curing Alzheimer’s by detecting elevated levels of APLP1 and CHL1 in a subject’s sample and treating the subject with a retromer therapeutic including a pharmacological chaperone or a composition comprising a transgene encoding VPS35.
Accordingly, the specification lacks enablement for preventing and curing Alzheimer’s by a) detecting APLP1, CHL1, and tau levels in a sample by an assay and comparing them to a reference amount from a healthy control, b) detecting the subject has retromer dysfunction if APLP1 and CHL1 are elevated in comparison to the healthy control samples, and c) treating the subject by administering a AAV9 vector comprising a transgene of VPS35 that has the amino acid sequence of instant SEQ ID NO: 1 and is operably linked to a promoter and/or treating the subject with pharmacological chaperone that i) is a small molecule, ii) binds at the interface between VPS35 and VPS29 and/or iii) is R55 or R33.
The state of the prior art:
The state of the art teaches treatment of a model of Alzheimer’s (AD) induced by retromer dysfunction in vivo by administering a viral vector encoding human VPS35; repletion of VPS35 normalized APP processing and restored levels of GluA1 (Qureshi et al., Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus, 2019, bioRxiv, pgs. 1-30; see instant IDS 10/26/2023). The state of the art does not teach these findings translate into alleviation of behavioral symptoms or that this method could restore damage in patients suffering from the disease sufficient to cure them. Furthermore, the state of the art is directed to disease models and does not address whether exogenous administration of VPS35 to healthy individuals would have a protective effect to prevent AD onset.
In short, there is no evidence to suggest that this method can be used to prevent or cure Alzheimer’s.
Glass (Aging Reimagined Can We Find a Cure for Alzheimer’s Disease?, 2024, The Brink, pgs. 1-19; see instant PTO-892) teaches that years after the filing date therapeutic options for Alzheimer’s disease do not prevent or cure it; therefore, one of ordinary skill in the art would not have been enabled to cure Alzheimer’s with claimed method as of the instant effective filing date. See MPEP 2164.05(a).
The amount of direction provided by the inventor:
The disclosure does not teach any working examples directed to treating, preventing, or curing Alzheimer’s by administering a pharmacological chaperone or administering a transgene encoding VPS35.
The only working example in the specification directed toward treating a condition administers a viral vector for a different retromer subunit, VPS26b (Example 17, pg. 96).
Furthermore, the specification admits that the biomarkers, APLP1 and CHL1, predominantly identify individuals who already meet the criteria for prodromal Alzheimer’s Disease (AD) (pg. 34, last three lines of second paragraph). Therefore, one of ordinary skill in the art would not have a reasonable expectation of success preventing AD using biomarkers that identify individuals who already have the condition.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
Given the breadth of the claims, lack of enablement in the state of the art, and the limited direction provided by the inventor, a significant quantity of experimentation would be required to use the invention. Further in vivo studies would need to address a variety of variables in order to provide enablement for curing and preventing Alzheimer’s, including but not limited to whether exogenous administration of VPS35 or a pharmacological chaperone is effective long term, influences behavioral symptoms, and whether these techniques protect against damage in addition to remediating it.
One of ordinary skill in the art would recognize that finding a cure or prevention for Alzheimer’s is a pinnacle goal in the field of neuroscience; based on the current disclosure and the state of the art, curing or preventing AD as recited in the instant claims would itself be its own advancement in the field, as it would require undue experimentation to determine if it is even possible.
Conclusion:
The specification is enabling for treating Alzheimer’s by detecting elevated levels of APLP1 and CHL1 in a subject’s sample and treating the subject with a retromer therapeutic including a pharmacological chaperone or a composition comprising a transgene encoding VPS35, but not for preventing or curing AD.
Claims 10 and 11 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. This is a written description rejection.
Claims 10 and 11 a method of treating Alzheimer’s in subjects with elevated levels of APLP1 and CHL1 by treating the subject with a composition comprising a transgene encoding VPS35 with an amino acid sequence at least 85% and 70%, respectively, identity to instant SEQ ID NO: 1.
Instant SEQ ID NO: 1 is 796 amino acids in length. Accordingly, both claims recite a vast genus of transgene sequences encoding VPS35, which all must be able to bind to other retromer subunits in order to treat Alzheimer’s.
The State of the Art:
The state of the art teaches treatment of retromer dysfunction Alzheimer’s in vivo by administering a viral vector encoding the human sequence of VPS35, which is equivalent to instant SEQ ID NO: 1 (Qureshi et al.; instant IDS 10/26/2023). However, the prior art at the time of filing does not teach repletion of VPS35 by viral expression of variants of SEQ ID NO: 1.
The state of the art also teaches how a single mutation in the retromer subunit VPS35 can impair binding to another retromer subunit VPS29, that affects the function of the entire retromer complex; this specific mutation in the VPS35 subunit has been linked to Parkinson’s pathogenesis (Zavodszky et al., Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy, 2014, Nature Communications pgs. 1-16, see instant PTO-892).
Therefore, the state of the art does not demonstrate possession of the claimed genera but demonstrates that single mutations in the binding regions of the retromer subunit can have drastic impacts on overall function of the retromer complex.
Description of representative species in the specification:
When the state of the art does not demonstrate possession of the recited claim, Applicant may demonstrate possession by teaching a representative number of species in the disclosure.
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case, the disclosure teaches one transgene with a modified human VPS35 encoding sequence, namely SEQ ID NO: 10 (pg. 49). However, the instant disclosure has no working examples drawn toward repletion of administration of a vector comprising the human VPS35 transgene or any variants of the human VPS35 sequence.
The teaching of one modified VPS35 sequence, namely SEQ ID NO: 10, is not sufficient to constitute the vast genera claimed.
To demonstrate how large the recited genera are, claim 10 will be used as an example. Claim 10 recites a nucleic acid encoding VPS35 with up to 15% variation of the amino acid sequence of SEQ ID NO: 1. Therefore, the amino acid (AA) sequence of the encoded VPS35 can have up to 119 AAs changed at any position of the 796 AA long sequence, each of which may be substituted to any of the other 19 AAs. Accordingly, there are an infinite number of ways to select which 119 amino acids from SEQ ID NO: 1 and then replace them with one of the remaining 19 amino acids.
Identifying characteristics and structure/function correlation:
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
In the instant case however, the claims permit variation at any point in the VPS35 amino sequence, including the binding residues for the other retromer subunits, VPS26a, VPS26b, and VPS29. There is no discussion in the specification that addresses what structural components (i.e. amino acid resides) must be preserved in each species in order to preserve functionality of the retromer complex that such it would treat Alzheimer’s. The specification does not address the evidence in the art that a single point mutation in a binding region for just one of the other retromer subunits can lead to drastic effects of the entire retromer complex’s function. Thus, one of ordinary skill would not envisage a VPS35 peptide with such drastic variation in the amino acid sequence, particularly in the binding regions, to maintain its function such that it would treat Alzheimer’s.
Given the immense breadth of the recited genera, the state of the art, the lack of examples directed to VPS35 sequence variations, and the lack of necessary structural features to achieve the claimed function, one of ordinary skill in the art would not be able to immediately envisage possession of the recited genera.
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(s) 1, 3-5, 9-11, 18, 20, and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Qureshi (Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus, 2019, bioRxiv, pgs. 1-30; see instant IDS 10/26/2023), in view of Neufeld (Biomarkers of Alzheimer-Associated Endosomal Dysfunction, 2018, Columbia University, pgs. 1-130; see instant IDS 10/26/2023; hereafter “Neufeld”), as evidenced by Hillman et al.. US6124446A (see instant PTO-892).
Qureshi et al. teaches the VPS35 and other retromer proteins are deficient in late-onset Alzheimer’s disease (AD) patients (pg. 3, second paragraph) and thought to be causal in Alzheimer’s symptoms. Furthermore, reduction in VPS35 results in increased levels of APP and its cleavage (pg. 2, second paragraph). Regarding claims 1,3, 18, and 20, Qureshi et al. teaches successful repletion of the human VPS35 protein via a AAV9 vector in neuronal culture (pg. 5) and in mouse hippocampus (pg. 6; second paragraph). Regarding instant claims 9-11, as evidenced by Hillman, the human VPS35 protein of Qureshi is comprised of the same sequence as instant SEQ ID NO:1 (see below). Importantly, Qureshi et al. teaches that the exogenous VPS35 retained functionality to bind to other retromer core proteins (pg. 6, last line of second paragraph). In a mouse model of hippocampal VPS35 depletion, exogenous repletion of VPS35 via a AAV9 vector decreased APP cleavage (pg. 7, first paragraph). Regarding claim 21, Qureshi et al. teaches the cytomegalovirus chicken beta-actin hybrid promoter was used to induce expression of the VPS35 transgene into a neural cell (pg. 11, second paragraph). Qureshi successful results provide support for a therapeutic approach of VPS35 repletion via viral vectors to treat AD (pg. 9, last paragraph).
Qureshi et al. does not teach isolating protein from a sample from a subject, detecting the level of the N-terminal fragment of CHL1, comparing the amount of the N-terminal fragment of CHL1 from the sample to a reference amount from a healthy control, detecting of the N-terminal fragment of APLP1 from the sample, comparing the amount of N-terminal fragment of APLP1 to a reference amount from a healthy control, and detecting that the subject has retromer dysfunction and/or endosomal trafficking dysfunction when the amount of N-terminal fragments of APLP1 and CHL1 are increased compared to their respective reference amounts.
Neufeld teaches that endosomal dysfunction, specifically retromer dysfunction (pg. 18, middle paragraph; pg. 19, second paragraph), is mechanistically linked to Alzheimer’s Disease (AD) (abstract) and that mice without VPS35, the core subunit of the retromer protein, exhibit symptoms of AD such as accumulation of Aβ peptides, as well as disruptions in long-term potentiation and memory (pg. 20, second paragraph). Regarding claims 1 and 3, Neufeld teaches isolating protein from a CSF sample (pg. 57, last two paragraphs; pg. 58, second paragraph; Fig. 4.5 caption). Neufeld teaches that N-terminal fragments of BACE1 substrates CHL1 and APLP1 were detected and elevated in the CSF of VPS35 knockout mice in comparison to healthy control levels (pg. 69, Fig. 4.8a). Regarding claim 5, Neufeld teaches that CHL1 and APLP1 were detected by an assay (pg. 76, last paragraph; Fig. 4.15). Regarding claim 3 part (f), Neufeld teaches that elevated levels of CHL1 and APLP1 are directly indicative of increased BACE1 activity due to retromer-dependent endosomal dysfunction (pg. 89, second paragraph) in VPS35 depleted models. Regarding claim 4, Neufeld teaches an increase in total tau in VPS35 knockout mice in comparison to controls (pg. 74, 4.12). Furthermore, Neufeld teaches a correlation between APLP1 and tau in plaque-free human CSF (pg. 89, last page). Regarding claims 1, 3, and 5, Neufeld suggests CHL1 and APLP1 as biomarkers for retromer dysfunction in early AD patients who are plaque free (pg. 82, second paragraph); Neufeld suggests tau as a biomarker for disease progression because unlike CHL1 and APLP1, it does not bind to plaque build-up in the brain and therefore would still be detectable in the CSF as a patient’s condition worsens (pg. 90, first paragraph). Lastly, Neufeld suggests VPS35 repletion as a tactic to treat retromer deficiency induced endosomal dysfunction (pg. 90, middle paragraph).
It would be obvious to one of ordinary skill in the art to combine the method of treating retromer dysfunction in Alzheimer’s of Qureshi by administering an AAV9 vector containing a transgene encoding instant SEQ ID NO: 1 linked with a promoter, with a method of identifying the Alzheimer’s patient population with retromer dysfunction and monitoring disease progression via CHL1, APLP1 and tau biomarkers, as taught by Neufeld, to arrive at a method of treating Alzheimer’s disease by a) isolating protein from a CSF sample of a subject, b) detecting the level of the N-terminal fragment of CHL1 in the sample using an assay c) comparing the amount of N-terminal fragment of CHL1 in the sample to a reference amount of N-terminal fragment of CHL1 from a healthy control, d) detecting the level of the N-terminal fragment of APLP1 in the sample using an assay e) comparing the amount of N-terminal fragment of APLP1 in the sample to a reference amount N-terminal fragment of APLP1 from a healthy control, f) detecting the subject has retromer dysfunction when the amount of CHL1 and APLP1 N-terminal fragments are increased compared to their respective reference amounts, g) treating the subject with AAV9 vector containing a transgene encoding instant SEQ ID NO: 1 linked with a promoter, and h) detecting the amount of tau in the sample and comparing the amount to a reference amount of tau. One of ordinary skill in the art would be motivated to combine the teachings of Qureshi and Neufeld in order to identify the population of Alzheimer’s patients that would benefit from VSP35 repletion to treat retromer dysfunction. Furthermore, one of ordinary skill in the art would be motivated to detect tau in the subject’s sample following VPS35 repletion treatment because Neufeld teaches that tau can be used to assess disease progression of retromer dysfunction in Alzheimer’s. There would be a reasonable expectation of success combining a known method for treating the retromer dysfunction in Alzheimer’s patient population with a known method for identifying said patient population using CHL1 and APLP1 and assessing disease progression using tau because of the successful results taught by, Qureshi et al., in which human VPS35 expressed via an AAV9 vector retained its functionality and reduced the hallmarks of Alzheimer’s in vivo.
Instant SEQ ID NO: 1 identical to SEQ ID NO: 1 of Hillman et al.:
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841
449
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Greyscale
Claim(s) 1, 3-5, 23-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Neufeld (Biomarkers of Alzheimer-Associated Endosomal Dysfunction, 2018, Columbia University, pgs. 1-130; see instant IDS 10/26/2023; hereafter “Neufeld”), in view of Mecozzi et al. (Pharmacological chaperones stabilize retromer to limit APP processing, 2014, Nature Chemical Biology pgs. 443-449; see instant PTO-892).
The teachings of Neufeld are above.
Neufeld further suggests retromer-stabilizing chaperones to remediate retromer dysfunction (pg. 90, second paragraph).
Neufeld does not explicitly teach treating a subject with retromer dysfunction by administering a small molecule pharmacological chaperone that binds at the interface between VPS35 and VPS29. Furthermore, the modified method does not teach that the pharmacological chaperone is R55 or R33.
Mecozzi et al. teaches that the retromer is a protein complex made of subunits including VPS35, VPS26, and VPS29 (Fig. 1). Mecozzi teaches patients with Alzheimer’s are deficient in VPS35 and VPS26 subunits (pg. 1, left side, second paragraph, lines 3-5). Mecozzi et al. teaches that the interface between the VPS35 and VSP29 core subunits is the weak point of the heterotrimer structure (pg. 444, right side, third paragraph) and determined that molecules called pharmacological chaperones can bind to the weak interface to stabilize the overall complex (abstract) to prevent the subunit degradation (pg. 444, left side, first paragraph) characteristic of AD (pg. 443, left side, second paragraph). Mecozzi teaches R55, a small molecule pharmacological chaperone, significantly reduced the levels of Aβ peptides (ppg. 447, left side, first paragraph) and increased retromer levels (pg. 448, left side, first sentence of third paragraph). Mecozzi et al. also teaches that R55 reduced BACE1 activity, as indicated by increased APP processing via the α-secretase pathway (pg. 447, last paragraph, pg.448, first paragraph left side and fifth paragraph right side). Lastly, Mecozzi et al. suggests retromer stabilization via R55 as a therapeutic route for AD (pg. 449, left side, first paragraph).
It would be obvious to one of ordinary skill in the art to combine the method of treating retromer dysfunction in Alzheimer’s of Mecozzi by administering R55 to a subject, with a method of identifying the Alzheimer’s patient population with retromer dysfunction and monitoring disease progression via CHL1, APLP1 and tau biomarkers of Neufeld, to arrive at a method of treating Alzheimer’s disease by a) isolating protein from a CSF sample of a subject, b) detecting the level of the N-terminal fragment of CHL1 in the sample using an assay c) comparing the amount of N-terminal fragment of CHL1 in the sample to a reference amount of N-terminal fragment of CHL1 from a healthy control, d) detecting the level of the N-terminal fragment of APLP1 in the sample using an assay e) comparing the amount of N-terminal fragment of APLP1 in the sample to a reference amount N-terminal fragment of APLP1 from a healthy control, f) detecting the subject has retromer dysfunction when the amount of CHL1 and APLP1 N-terminal fragments are increased compared to their respective reference amounts, g) treating the subject with R55, which is a small molecule pharmacological chaperone that binds at the interface of VPS29 and VPS35. One of ordinary skill in the art would be motivated to combine the teachings of Neufeld and Mecozzi et al. because i) the CHL1 and APLP1 biomarkers taught by Neufeld can identify the patient population likely to benefit from retromer stabilization, ii) Neufeld explicitly suggests pharmacological chaperones as a method of restoring retromer function in AD, iii) Mecozzi et al. teaches a retromer stabilization via specific pharmacological chaperone, namely R55, as a therapeutic route for AD and iv) the tau biomarker taught by Neufeld can monitor disease progression of retromer dysfunction in AD. There would be a reasonable expectation of success treating Alzheimer’s patients identified by APLP1 and CHL1 biomarkers by administering R55 because of the successful results taught by Mecozzi et al.
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, 3, 4, 5, 9-11,18, 20, 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3, 15, 17, 20, 22, 29, 35, 37, 40, 46, 49, 60-66 of copending Application No. 17/782,357 (reference application), in view of Neufeld (Biomarkers of Alzheimer-Associated Endosomal Dysfunction, 2018, Columbia University, pgs. 1-130; see instant IDS 10/26/2023; hereafter “Neufeld”) and Qureshi (Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus, 2019, bioRxiv, pgs. 1-30; see instant IDS 10/26/2023). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 3, 15, 17, 20, 22, 29, 30, 37, 40, 46, 49, and 60-66 of the reference application teach a method of increasing retromer function in a neuronal cell by administering a vector comprising the transgene encoding retromer core protein VPS35, which is identical to instant SEQ ID NO:1, to a neuronal cell, thereby increasing the levels of VPS35 and VPS26a retromer core proteins. Claims 69 and 65 also teach that the vector is an AAV9.
The reference application does not teach detecting biomarkers CHL1, APLP1, and tau in a subject’s isolated sample and comparing them to a reference sample using an assay. The reference application does not teach detecting the subject has retromer dysfunction as demonstrated by elevated levels of CHL1 and APLP1.
The teachings of Neufeld and Qureshi et al. are described previously.
It would be obvious to one of ordinary skill in the art to combine the method of increasing retromer function in a neuronal cell by administering an AAV9 vector comprising the transgene encoding instant SEQ ID NO: 1, as taught by the reference application, with a method of detecting retromer dysfunction in AD and monitoring disease progression in a subject with CHL1, APLP1 and tau, as taught by Neufeld, in order to arrive at a method of treating Alzheimer’s comprising a) isolating protein from a CSF sample of a subject, b) detecting the level of the N-terminal fragment of CHL1 in the sample using an assay c) comparing the amount of N-terminal fragment of CHL1 in the sample to a reference amount of N-terminal fragment of CHL1 from a healthy control, d) detecting the level of the N-terminal fragment of APLP1 in the sample using an assay e) comparing the amount of N-terminal fragment of APLP1 in the sample to a reference amount N-terminal fragment of APLP1 from a healthy control, f) detecting the subject has retromer dysfunction when the amount of CHL1 and APLP1 N-terminal fragments are increased compared to their respective reference amounts, g) treating the subject with AAV9 vector containing a transgene encoding instant SEQ ID NO: 1 linked with a promoter, and h) detecting the amount of tau in the sample and comparing the amount to a reference amount of tau. One of ordinary skill in the art would be motivated to combine these teachings because Neufeld teaches APLP1, CHL1 and tau are biomarkers for VPS35 retromer dysfunction and disease progression in AD patients and suggests viral VPS35 repletion as a strategy for repletion, while the reference application teaches a method of VPS35 repletion. There would be a reasonable expectation of success combining a method of identifying a patient population, as taught by Neufeld, with a method of treating that patient population, as taught by the reference application, because of the successful results of VPS35 repletion taught by Qureshi et al..
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 3, 23-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3, 15, 17, 20, 22, 29, 35, 37, 40, 46, 49, 60-66 of copending Application No. 17/782,357 (reference application), in view of Neufeld (Biomarkers of Alzheimer-Associated Endosomal Dysfunction, 2018, Columbia University, pgs. 1-130; see instant IDS 10/26/2023; hereafter “Neufeld”) and Qureshi (Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus, 2019, bioRxiv, pgs. 1-30; see instant IDS 10/26/2023), as applied to instant claim 3 above, in further view of Mecozzi et al. (Pharmacological chaperones stabilize retromer to limit APP processing, 2014, Nature Chemical Biology pgs. 443-449; see instant PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other.
The modified method of treating Alzheimer’s as taught by reference application ‘357, Neufeld, and Qureshi et al. comprises a) isolating protein from a CSF sample of a subject, b) detecting the level of the N-terminal fragment of CHL1 in the sample using an assay c) comparing the amount of N-terminal fragment of CHL1 in the sample to a reference amount of N-terminal fragment of CHL1 from a healthy control, d) detecting the level of the N-terminal fragment of APLP1 in the sample using an assay e) comparing the amount of N-terminal fragment of APLP1 in the sample to a reference amount N-terminal fragment of APLP1 from a healthy control, f) detecting the subject has retromer dysfunction when the amount of CHL1 and APLP1 N-terminal fragments are increased compared to their respective reference amounts, g) treating the subject with AAV9 vector containing a transgene encoding instant SEQ ID NO: 1 linked with a promoter, and h) detecting the amount of tau in the sample and comparing the amount to a reference amount of tau.
The modified method of reference application ‘357, Neufeld, and Qureshi et al. does not teach that method of treating Alzheimer’s further comprises administering a pharmacological chaperone that is a small molecule, binds at the interface of VPS29 and VPS35 and/or is R55.
The teachings of Mecozzi et al. are described above.
It would be obvious to one of ordinary skill in the art to combine the method of treating AD of modified reference application, Neufeld, and Qureshi et al., with administration of the small molecule pharmacological chaperone R55, which binds at the interface between VPS35 and VPS29, as taught by Mecozzi et al., to arrive at a method of treating Alzheimer’s by comprising a) isolating protein from a CSF sample of a subject, b) detecting the level of the N-terminal fragment of CHL1 in the sample using an assay c) comparing the amount of N-terminal fragment of CHL1 in the sample to a reference amount of N-terminal fragment of CHL1 from a healthy control, d) detecting the level of the N-terminal fragment of APLP1 in the sample using an assay e) comparing the amount of N-terminal fragment of APLP1 in the sample to a reference amount N-terminal fragment of APLP1 from a healthy control, f) detecting the subject has retromer dysfunction when the amount of CHL1 and APLP1 N-terminal fragments are increased compared to their respective reference amounts, g) treating the subject with AAV9 vector containing a transgene encoding instant SEQ ID NO: 1 linked with a promoter, and h) detecting the amount of tau in the sample and comparing the amount to a reference amount of tau and i) administering R55. One of ordinary skill in the art would be motivated to combine the teachings of modified method of treating Alzheimer’s taught by the reference application, Neufeld and Qureshi et al. with Mecozzi et al. because both methods seek to increase retromer complex levels in order to treat Alzheimer’s disease. One of ordinary skill in the art would have a reasonable expectation of success combining two known methods for increasing retromer complex in Alzheimer’s disease. One of ordinary skill in the art would anticipate that these methods would have a synergistic effect, where the repletion of VPS35 subunits (i.e. via the viral vector) enhances the ability of the pharmacological chaperone to stabilize VPS35 subunits with VPS29 subunits.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 4, 5, 9-11, 18, 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-58 of Application No.19/638,366, in view of Neufeld (Biomarkers of Alzheimer-Associated Endosomal Dysfunction, 2018, Columbia University, pgs. 1-130; see instant IDS 10/26/2023; hereafter “Neufeld”), and Qureshi (Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus, 2019, bioRxiv, pgs. 1-30; see instant IDS 10/26/2023). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1-14 and 29-34 of the reference application teach a method of treating, preventing, and or curing a neurodegenerative disease, wherein the disease is Alzheimer’s, by administering an effective amount of a viral vector comprising a transgene encoding the retromer core protein VPS35, wherein the vector is AAV9. Claims 15-58 teach a vector, composition and kit comprising a viral vector comprising a transgene encoding the retromer core protein VPS35 with the same sequence as instant SEQ ID NO: 1, wherein the transgene is operably linked to a promoter that induces expression of the transgene in a neural cell.
The reference application does not teach that that the method of treating Alzheimer’s specifically comprises detecting elevated levels of CHL1, APLP1, and tau using an assay. The reference application does not teach detecting a subject has retromer dysfunction as demonstrated by elevated levels of CHL1 and APLP1.
The teachings of Neufeld and Qureshi et al. are above.
It would be obvious to one of ordinary skill in the art to combine the method of treating retromer dysfunction in Alzheimer’s of the reference application by administering an AAV9 vector containing a transgene encoding instant SEQ ID NO: 1 linked with a promoter, with a method of detecting retromer dysfunction in AD and monitoring disease progression in a subject with CHL1, APLP1 and tau, as taught by Neufeld, in order to arrive at a method of treating Alzheimer’s comprising a) isolating protein from a CSF sample of a subject, b) detecting the level of the N-terminal fragment of CHL1 in the sample using an assay c) comparing the amount of N-terminal fragment of CHL1 in the sample to a reference amount of N-terminal fragment of CHL1 from a healthy control, d) detecting the level of the N-terminal fragment of APLP1 in the sample using an assay e) comparing the amount of N-terminal fragment of APLP1 in the sample to a reference amount N-terminal fragment of APLP1 from a healthy control, f) detecting the subject has retromer dysfunction when the amount of CHL1 and APLP1 N-terminal fragments are increased compared to their respective reference amounts, g) treating the subject with AAV9 vector containing a transgene encoding instant SEQ ID NO: 1 linked with a promoter, and h) detecting the amount of tau in the sample and comparing the amount to a reference amount of tau. One of ordinary skill in the art would be motivated to combine these teachings because Neufeld teaches APLP1, CHL1 and tau as biomarkers for VPS35 retromer dysfunction and disease progression in AD patients and suggests viral VPS35 repletion, while the reference application teaches a method for VPS35 repletion. Therefore, APLP1 and CHL1, as taught by Neufeld, can identify the patient population likely to benefit from VPS35 retromer repletion treatment. There would be a reasonable expectation of success treating Alzheimer’s patients with retromer dysfunction, identified by APLP1 and CHL1 biomarkers, by repletion of VPS35 via a viral vector because of the successful results taught by, Qureshi et al., in which VPS35 expressed via an AAV9 vector retained its functionality and reduced the hallmarks of Alzheimer’s in vivo.
Claims 3, and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-58 of Application No.19/638,366, in view of Neufeld (Biomarkers of Alzheimer-Associated Endosomal Dysfunction, 2018, Columbia University, pgs. 1-130; see instant IDS 10/26/2023; hereafter “Neufeld”), and Qureshi (Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus, 2019, bioRxiv, pgs. 1-30; see instant IDS 10/26/2023), as applied to claim 3 above, and Mecozzi et al. (Pharmacological chaperones stabilize retromer to limit APP processing, 2014, Nature Chemical Biology pgs. 443-449; see instant PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other.
The modified method of treating Alzheimer’s as taught by reference application ‘366, Neufeld, and Qureshi et al. teaches a) isolating protein from a CSF sample of a subject, b) detecting the level of the N-terminal fragment of CHL1 in the sample using an assay c) comparing the amount of N-terminal fragment of CHL1 in the sample to a reference amount of N-terminal fragment of CHL1 from a healthy control, d) detecting the level of the N-terminal fragment of APLP1 in the sample using an assay e) comparing the amount of N-terminal fragment of APLP1 in the sample to a reference amount N-terminal fragment of APLP1 from a healthy control, f) detecting the subject has retromer dysfunction when the amount of CHL1 and APLP1 N-terminal fragments are increased compared to their respective reference amounts, g) treating the subject with AAV9 vector containing a transgene encoding instant SEQ ID NO: 1 linked with a promoter, and h) detecting the amount of tau in the sample and comparing the amount to a reference amount of tau.
The modified method of reference application ‘366, Neufeld, and Qureshi et al. does not teach that method of treating Alzheimer’s further comprises administering a pharmacological chaperone that is a small molecule, binds at the interface of VPS29 and VPS35 and/or is R55.
The teachings of Mecozzi et al. are described above.
It would be obvious to one of ordinary skill in the art to combine the method of treating AD of modified reference application, Neufeld, and Qureshi et al., with administration of the small molecule pharmacological chaperone R55, which binds at the interface between VPS35 and VPS29, as taught by Mecozzi et al., to arrive at a method of treating Alzheimer’s by comprising a) isolating protein from a CSF sample of a subject, b) detecting the level of the N-terminal fragment of CHL1 in the sample using an assay c) comparing the amount of N-terminal fragment of CHL1 in the sample to a reference amount of N-terminal fragment of CHL1 from a healthy control, d) detecting the level of the N-terminal fragment of APLP1 in the sample using an assay e) comparing the amount of N-terminal fragment of APLP1 in the sample to a reference amount N-terminal fragment of APLP1 from a healthy control, f) detecting the subject has retromer dysfunction when the amount of CHL1 and APLP1 N-terminal fragments are increased compared to their respective reference amounts, g) treating the subject with AAV9 vector containing a transgene encoding instant SEQ ID NO: 1 linked with a promoter, and h) detecting the amount of tau in the sample and comparing the amount to a reference amount of tau and i) administering R55. One of ordinary skill in the art would be motivated to combine the teachings of modified method of treating Alzheimer’s taught by the reference application, Neufeld and Qureshi et al. with Mecozzi et al. because both methods seek to increase retromer complex levels in order to treat Alzheimer’s disease. One of ordinary skill in the art would have a reasonable expectation of success combining two known methods for increasing retromer complex in Alzheimer’s disease. One of ordinary skill in the art would anticipate that these methods would have a synergistic effect, where the repletion of VPS35 subunits (i.e. via the viral vector) enhances the ability of the pharmacological chaperone to stabilize VPS35 subunits with VPS29 subunits.
Conclusion
No claims allowed.
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/MICHELLE CALLAHAN BUCCINI/Examiner, Art Unit 1675
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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