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 .
Applicant’s reply dated 5/6/26 has been received.
Claims 157-160,167,169-176 are pending and under consideration.
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 157-160,167,169-176 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.
Claim 157 recites “Ab peptide variant comprises an amino acid sequence…”. It is unclear if Applicant intends for the claim to encompass fragments of the sequences recited. Applicant has removed the reduced identity language to narrow the claims to the specifically recited sequences and thus, the phrase “an amino acid sequence set forth by SEQ ID NO:…” should read “the amino acid sequence set forth by SEQ ID NO:…”.
Claims 158-160,167,169-176 are included by virtue of their dependency from claim 157.
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 157-160,167,169-176 remain 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 a method of treating or preventing amyloid b peptide aggregation and symptoms associated with Ab aggregation in the brain of a subject having a mutation associated with amyloid b peptide aggregation comprising administering to the subject by intraventricular injection, a vector encoding a variant Ab peptide comprising the sequence set forth by SEQ ID NO:4 operably linked to a constitutive promoter and further comprising a signal peptide sequence and a transmembrane and cytosolic sequence, wherein the variant Ab is expressed and leads to reduced Ab deposition and aggregation, and reduced neuroinflammation, does not reasonably provide enablement for carrying out the claimed method for any neurodegenerative disease, use of any of the claimed Ab variants other than that comprising SEQ ID NO:4, or vectors lacking the signal, transmembrane and cytosolic sequence. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
The nature of the invention relates to gene therapy to reduce the accumulation of amyloid b (Ab) in the brain. The invention utilizes variants of Ab that are less prone to aggregate to prevent the aggregation of wildtype Ab42 that occurs in Alzheimer’s Disease and animal models of Alzheimer’s Disease.
The claims are broad in a number of respects. First, they are drawn to treating and preventing any neurodegenerative disease. The claims are also broad with regard to the identity of the vector, the mode of delivery and the variant encoded. Finally, the claims are unlimited with regard to the treatment effect and thus in treating neurodegenerative disease, the claims encompass treating or preventing symptoms of Parkinson’s, Huntington’s, and ALS (tremors, paralysis) as well as any and all symptoms of Alzheimer’s Disease.
The Specification teaches assessing both in vitro and in vivo effects of 5 Ab peptide variants. Four have a single amino acid substitution and the fifth has 2 amino acid substitutions. One variant, V18P, was found to exacerbate fibril formation in vitro and was not included for further study. The remaining four are recited in claim 1 and are represented by SEQ ID NO:s 3-6. Each of the four were found to reduce fibril formation in vitro (see para 278). Two peptide variants, F20P and F19D/L34P) were found to completely prevent aggregation and only these two were studied further and included in in vivo studies.
The Specification teaches peptide expression was driven by the constitutive CAG promoter (para 282) to provide lifelong expression of the Ab variant. The Specification teaches that transgenic models of Alzheimer’s Disease treated by injection with the vector encoding the F20P variant showed almost 75% decrease in Ab deposition compared to uninjected control model. The effects of F19D/L34P were more variable and Ab42 and plaque load were not found to be diminished despite positive findings in the in vitro studies (para 287). Detection of Ab42 was inhibited in experiments using the F19D/L34P, possibly due to lack of antibody recognition. Thus, data from those experiments were difficult to interpret.
Post-filing, Park (2021, Molecular Therapy, 29:2294-2307; IDS) discusses how the in vitro findings relating to the four, studied variants did not necessarily correlate to in vivo efficacy. The F19D/L34P was the best in vitro candidate but it turned out to be less effective and variable with inconclusive in vivo results compared to F20P (see page 2300, right column).
With regard to the Ab peptide variants encompassed by the claims, those represented by SEQ ID NO:s 3-6 are discussed above. The claims also encompass variants of those sequences (80%, claim 1), claimed as “a fragment or functional derivative thereof” with dependent claims 162-165 reciting as little as 85% sequence identity. Given that the Specification tested 5 sequences with only one AA difference from one another and this one AA change could exacerbate fibril formation (V18P) or reduce plaque and fibril formation in vivo (F20P), with F19D/L34P giving somewhat contradictory in vitro and in vivo results, the Specification fails to support use of these variants to treat neurodegenerative disease as claimed or to reduce Ab aggregation in an Alzheimer’s model as shown for the F20P variant.
The Specification also teaches that to carry out the invention, the peptide must be delivered to the cell membrane and be cleaved by g-secretase. The Specification teaches that the signal peptide sequence, the transmembrane domain and cytosolic KK amino acids are both necessary and sufficient (para 281) and thus, each component should be included.
With regard to recited effects (claim 158), the Specification supports reduced plaque and Ab formation. However, many of the latter examples are prophetic and fail to support recited effects such as decreased tau levels (para 317), for example. Claim 160 recites that cytotoxicity may be prevented or decreased. Para 297, however, states that the variants may abate cytotoxicity of wildtype aggregates and discusses how it can be assayed. However, no testing appears to have been carried out.
Thus, given the guidance in the Specification along with the teachings in the art both pre- and post- filing, it would require undue experimentation to treat any and all symptoms of any neurodegenerative disease or treat Ab aggregation using the variety of variants encompassed by the claims.
Component of the vector-With regard to the aspect of the rejection relating to inclusion of a signal sequence (membrane targeting), Applicant points to paragraph 281 that indicates that the inclusion of a TM and only 2 cytosolic amino acids are necessary and sufficient for Ab secretion at levels observed for full-length CTF. Paragraph 281 refers to Figure 2a, which shows the presence of the signal peptide and states that a g-secretase inhibitor prevents release of the Ab into the media. Because g-secretase cleavage is necessary and it occurs at the membrane, it is maintained that the signal sequence, which targets the protein to the membrane, is necessary. Applicant is directed to paragraph 280 for support that a signal sequence is present in the experiments referenced in para 281 (Gaussia luciferase signal peptide).
Scope of Neurodegenerative Diseases-Applicant argues that the method of the invention prevents Ab aggregation, plaque formation, neuroinflammation, neurodegeneration, neuronal loss, decreased tau levels…and/or promote cognitive improvement (para 42). Applicant continues by referencing para 43 states that the method treats neurodegenerative disorder or inhibiting aggregation of endogenous ab peptide. Para 43 continues that in some embodiments the neurodegenerative disease is Alzheimer’s Parkinson’s vascular dementia…Down Syndrome, and/or pathological aging. These recitations in the Specification are prophetic and use alternative language. The list of diseases is merely a laundry list of a variety of neurodegenerative diseases. Down Syndrome is associated with a higher risk of premature neurodegeneration from overproduction of amyloid-beta but plaque formation is not a cause Down Syndrome, which is present at birth (see Marks, 2022, UCSF Research, Down Syndrome, Like Alzheimer’s, Is a Double-Prion Disorder | UC San Francisco, https://www.ucsf.edu/news/2022/11/424241/down-syndrome-double-prion-disorder-alzheimers). The Specification supports reduced plaque and Ab formation. However, many of the latter examples are prophetic and fail to support recited effects such as decreased tau levels (para 317), for example. Claim 160 recites that cytotoxicity may be prevented or decreased. Para 297, however, states that the variants may abate cytotoxicity of wildtype aggregates and discusses how it can be assayed. However, no testing appears to have been carried out. Thus, the Specification teaches preventing amyloid-b peptide aggregation but does not go so far as to supporting treatment of various and disparate neurodegenerative diseases such as Parkinson’s and pathological aging. These other diseases have other or additional causes and decreasing Ab secretion using the claimed method does not support treatment of the claimed genus. Applicant provides paragraphs 43,45-46, and 57 of the Specification which discuss various claimed diseases. Applicant concludes that the Examples of the present disclosure demonstrate that the vector encoding the Ab peptide variant exhibits effects of reducing Ab burden and neuroinflammation. This conclusion is not commensurate with the claims which are drawn to treatment of numerous neurodegenerative diseases, not just reducing b burden and neuroinflammation.
Route of Administration- This aspect of the rejection is withdrawn in light of the amendments to the claims and applicant’s Remarks.
Applicant does not appear to have addressed the aspects of the rejection involving inclusion of a constitutive promoter to drive gene expression or that the Specification on teaches an in vivo reduction of Ab for SEQ ID NO:4.
Claim Rejections - 35 USC § 112
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.
The rejection of claims 157-176 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 is withdrawn. Applicant has deleted the variant, fragments and derivative language from claim 1. Applicant provides arguments with regard to sequences set forth by SEQ ID NO:2,4,5, and 6 and points to support in the Specification that these sequences inhibit fibril formation in vitro. This is an issue set forth under enablement as Applicant has described the sequences now claimed. As set forth above, the Specification only supports the claimed activity, in vivo, for the sequence set forth by SEQ ID NO:4.
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 157,171-174,158 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,3-5,8-9,11-14,17-18,25,29 of copending Application No. 18/274,634 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘634 application claims a combination of 2 treatments that includes the currently claimed Ab variant treatment whereby neither claim 1 of ‘634 or independent, base claim 157 of the instant application require an effect. Therefore, it would be obvious to carry out the method of ’634 with just the Ab peptide variant to determine the effective contribution of each treatment in the combination. Dependent claims of each application limit the sequences (SEQ ID NO:3-6 in the instant case and 17-20 in ‘634). Instant claim 161 and reference claims 17-18 limit the disease with those of instant claim 161 being recited in reference claims 17-18.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant has not responded to this rejection because it is providsional.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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