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 .
Claims 157-176 are pending and under consideration.
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.
Claims 157-176 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 a method of treating or preventing amyloid b peptide aggregation and symptoms associated with Ab aggregation in the brain of a subject having mutation associated with amyloid b peptide aggregation comprising administering to the subject by injection into the lateral ventricle, an AAV 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, vectors lacking the signal, transmembrane and cytosolic sequence, or any mode of delivery other than direct injection into the lateral ventricle of the brain. 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 when amyloid accumulation is associated with Alzheimer’s 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 continues with vector design as it was known in the art at the time of the invention that delivery of peptides across the BBB and proteolytic degradation of peptides was problematic (see Lalatsa, 2014, Mol. Pharm. 11:1081-1093). Zhang (2018, Biomaterials, 176:71-83) teaches that AAV8, alone, does not efficiently cross the BBB and shuttle peptides are needed. The Specification teaches deliver of an AAV8 vector encoding Ab to the brain via injection directly into the lateral ventricle (para 283, 302). The 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.
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.
Claims 157-176 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.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or 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. “Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
In the instant case the claimed nucleic acids encoding variants, fragments and functional derivatives of the sequences set forth by SEQ ID NO:s 3-6 encompassed by the claims lack a written description. The specification fails to describe what nucleic acid molecules fall into this genus and it was unknown as of Applicants’ effective filing date that any of these molecules would have the properties established by the Specification for nucleic acid molecules encoding the sequences set forth by SEQ ID NO:s 3-6.
The specification, as filed, discloses that single amino acid substitutions in the central hydrophobic regions (that are represented by the sequences set forth in SEQ ID NO:s 3-6) alter the rate of fibril assembly in an unpredictable manner. The Specification explores 4 single amino acid variants and one double amino acid variant. However, the claims allow for variations up to 20%, along with truncations.
In Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004, screening assays were deemed insufficient in providing adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171).” Thus, having the ability to screen and obtain nucleic acid molecules that have the same functional properties as each of those set forth by SEQ ID NO:s 3-6 does not fulfill the requirement of Written Description. Knowledge of any potential screening methods provides no information regarding the structure of the many, extremely diverse members of the genus, and their function in affect amyloid deposits and fibril formation and the ability to affect neurodegenerative disease.
The specification describes that a polynucleotide encoding the sequence set forth by SEQ ID NO:4 can prevent Ab aggregation in vivo. The specification does not demonstrate or provide predictability for achieving this activity using any polynucleotide other than one encoding a protein comprising SEQ ID NO:4.
Therefore, considering the extremely large variation in the genus, the failure of the specification to describe or provide predictability for achieving any Ab42 variant other than that encoding the sequence of SEQ ID NO:4, and the lack of predictability provided by the art for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that “to fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention”.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
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 157,171-174,161,158 are 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.
Conclusion
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/ Primary Examiner, Art Unit 1632