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 .
Status of Claims
Claims 7-10, 16-18, 20, 24, 27, and 29-33 are cancelled.
Claims 1-6, 11-15, 19, 21-23, 25-26, and 28 are pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 04/22/2024 and 06/05/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Pages 14-15 recite SEQ ID NOs without a corresponding “sequence listing.”
Specification
The disclosure is objected to because of the following informalities:
On page 14, in the first line of the last paragraph, “anthanogene” should be “athanogene.”
On page 15, line 1, “invention can be a can be a variant” should be “invention can be a variant.”
Appropriate correction is required.
Claim Objections
Applicant is advised that should claim 12 be found allowable, claim 21 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claims 12-15, and 21 are objected to because of the following informalities:
In each of claims 12 and 21, line 3 of each, each of the promoters starting with “bicistronic promoter,” “tissue specific promoter,” or “cardiac specific promoter” is missing an article; i.e., “a bicistronic promoter,” “a tissue specific promoter,” or “a cardiac specific promoter.” Compare with “a constitutive promoter” in lines 2-3.
In claim 13, line 2, each of “cardiotropic vector” and “plasmid” is missing an article; i.e., “a cardiotropic vector” and “a plasmid”.” Compare with “a yeast vector” line 2.
In claim 14, line 3, each of the vectors starting with “cytomegalovirus vector, Epstein-Barr virus vector, parvovirus vector…” is missing an article; i.e., “a cytomegalovirus vector” “an Epstein-Barr virus vector, a parvovirus vector…”. Compare with “a coxsackie virus vector” in lines 2-3.
In claim 15, line 3, “AAV7m” should be “AAV7,”.
Appropriate correction is required.
Claim Interpretation
Claim 21 recites the term “optionally.” The limitations following optionally are being interpreted as not required by the claim when considering prior art.
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 1-6, 11-15, 19, 21-23, 25-26, and 28 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.
Per MPEP 2163, 35 U.S.C. 112(a) requires, “separate and distinct from the enablement requirement”, that the “specification shall contain a written description of the invention…” (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicants are claiming and what Applicants have possession of.
Regarding claim 1, 3-4, 11-15, 19, 21-23, 25-26, and 28:
The claimed invention is a method; specifically a method of reducing, inhibiting, or decreasing TNF signaling that requires administering a nucleic acid encoding a BAG3, BAG3 protein or BAG3 peptide.
The specification teaches that BAG3 (Bcl-2 associated athanogene) “is a cytoprotective polypeptide that competes with Hip-1 for binding HSP 70” (page 14), elsewhere described as “heat shock protein 70” (page 1). The specification at page 14 identifies the amino acid sequence of the human BAG3 that is known in the prior art as SEQ ID NO: 1 (575 amino acids), encoded by a nucleic acid sequence of SEQ ID NO: 2 (2,608 nucleic acids). On pages 14-15, SEQ ID NO: 3 (575 amino acids), SEQ ID NO: 4 (575 amino acids), SEQ ID NO: 5 (574 amino acids), and SEQ ID NO: 6 (575 amino acids) are taught to represent other BAG3 sequences known in the prior art without further description. Sequence alignment between SEQ ID NO: 1 and each of these sequences reveals that SEQ ID NO: 3 and 6 are 100% identical to SEQ ID NO: 1; SEQ ID NO: 4 differs from SEQ ID NO: 1 by one amino acid substitution; and SEQ ID NO: 5 differs from SEQ ID NO: 1 by one amino acid substitution and 1 amino acid deletion. No information is provided as to whether the mutated BAG3 proteins of SEQ ID NO: 4 or 5 retain functionality.
The specification further teaches that a BAG3 polypeptide of the invention “can be a variant of a polypeptide described herein, provided it retains functionality”. The specification further teaches that the terms ““polypeptides,” “proteins” and “peptides” encoded by the “polynucleotide sequences,” include full-length native sequences, as with naturally occurring proteins, as well as functional subsequences, modified forms or sequence variants so long as the subsequence, modified form or variant retains some degree of functionality of the native full-length protein”.
In view of the language recited in the claims, and the teachings of the specification, the claims encompass naturally-occurring BAG3 polypeptides, such as the human protein represented by SEQ ID NO: 1, as well as variants having one or more mutations in the naturally-occurring sequence, without limit. Furthermore, both the terms “BAG3 polypeptide” and “BAG3 peptide” each encompass fragments of BAG3 that retain the activity of the full-length protein. As such, the claims encompass use of a vast genus of BAG3 protein variants. As noted above, the human BAG3 consists of 545 amino acids, and thus variants of this sequence include those in which each position is replaced with any of the other 19 natural amino acids, either singly or in combination with mutations at each of the other positions. Even if just single amino acid substitutions are considered, the genus of potential structures encompasses 10,355 variants. Substitutions at each of the 525 residues of the protein includes up to 20545 variants, or 3.56 x 10708 variants. The genus of structures further includes every possible fragment of BAG3 in combination, with or without substitution mutations at each position.
As quoted above, the specification further indicates that variants of BAG3 should require functionality of the naturally-occurring protein, and the claimed method necessarily requires such for successful treatment. Thus, the product employed by the claimed method is defined structurally by its amino acid sequence, and functionally by its ability to function as a native BAG3 protein. However, a product defined by function is not in and of itself sufficient to describe the product because it is only an indication of what the product does, rather than what it is; i.e., the specific structure of the product. It is only a definition of a useful result rather than a definition of what achieves that result. Per MPEP 2124, "describing a composition by its function alone typically will not suffice to sufficiently describe the composition".
The prior art appreciates that "Mutations … are generally destabilizing, and can reduce protein … fitness" and "In general, more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation" (pg. 602 of Tokuriki et al, 2009, Current Opinion in Structural Biology. 19: 596-604). The prior art also appreciates that "the range of possible SNV [single nucleotide variation] effects at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge" (pg. 18 of Bhattacharya et al, 2017. Plos One. 12(3): e0171355, pages 1-22 as printed). Thus, knowledge of the sequence of a protein (e.g., a BAG3 protein having the amino acid sequence of SEQ ID NO: 1) is not sufficient for the skilled artisan at the time of the effective filing date to predict which substitution mutations will result in a protein having the required target activity.
Written description for a genus may also be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, in an unpredictable art, adequate description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Also, “[w]hen a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)). “[A] sufficient description of a genus … requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69). A description of a single species defined by its amino acid sequence is not representative of a genus encompassing thousands or more members having different structures. Per MPEP 2163, "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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")
In the instant case, the specification provides very limited guidance as to the nature of which members of the vast genus of BAG3 amino acid sequences encompassed by claim 1, its dependent claims, and claim 3 that will have the required functionality. As described above, the specification provides the naturally-occurring human sequence of BAG3, as well as two variant sequences with alterations at one or two positions (SEQ ID NO: 4 and 5). However, the specification does not even teach whether these variants retain the activity of the native BAG3 protein. Thus, the specification only describes a single example of a BAG3 protein having the functionality required for use in the claimed method of treatment; i.e., the amino acid sequence of SEQ ID NO: 1. While this sequence meets the written description requirement, it does not provide any description of other sequences in the vast genus of encompassed structures that also have the required functionality in binding to a particular target. The specification further does not describe any positions in BAG3 where amino acid mutations can be made without altering the activity of the protein.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (pg. 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg. 1116).
Therefore, only a method of claims 1, 3-4, and 11-15, 19, 21-23, 25-26, and 28, wherein the nucleic acid encodes a BAG3 protein having the amino acid sequence of SEQ ID NO: 1, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112(a). Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg. 1115).
Regarding claim 2 and 5-6:
The claimed invention is a method; specifically a method of treating inflammation that requires administering to the patient an amount of an agent that modulates expression or amount of BCL2-associated athanogene 3 (BAG3) encoding nucleic acid, BAG3 protein or BAG3 peptide.
Claim 2 recites “an agent.” The specification defines the term “agent” as “any molecule, chemical entity, composition, drug, therapeutic agent, or biological agent capable of preventing, ameliorating, or treating a disease or other medical condition. The term includes small molecule compounds, antisense reagents, siRNA reagents, antibodies, enzymes, peptides organic or inorganic molecules, natural or synthetic compounds and the like,” see pg. 15.
In view of the language recited in the claims, and the teachings of the specification, the claims encompass any matter, without limit, so long as it modulates (i.e., increase or decrease) expression or amount of BCL2-associated athanogene 3 (BAG3) encoding nucleic acid, BAG3 protein or BAG3 peptide.
Adequate written description support for a claimed genus may be provided by describing sufficient identifying characteristics, describing a representative number of species, actual reduction to practice, disclosure of drawings or structural chemical formulas, complete or partial structure, physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure and any working examples, method of making the claimed invention, level of skill and knowledge in the art as well as predictability in the art are other determinants that are used to analyze whether applicants had possession of the claimed genus. The present specification fails to meet these requirements for the following reasons.
In the instant case, the specification provides non-specific working examples of BAG3 siRNA (of an undisclosed sequence/structure and no corresponding SEQ ID NO) and BAG3 overexpression vector (of an undisclosed sequence/structure and no corresponding SEQ ID NO), see example 2: results. The specification provides no further guidance other than vaguely mentioning siRNA and BAG3 overexpression vector.
The prior art appreciates, for example, that siRNA and antisense oligonucleotide therapeutics employ different molecular structures, chemical modifications, mechanisms of action, and delivery requirements then small molecule inhibitors or biologics (Figure 1: Katzmann JL, et al., Targeting RNA With Antisense Oligonucleotides and Small Interfering RNA: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Aug 4;76(5):563-579).
A person of ordinary skill in the art would not be able to envision from the guidance in the specification or the prior art at a common core structural feature that would be predictive of the vast array of species within the genus of “an agent” that would exhibit the claimed functional limitation of modulating (either upregulation or downregulation) expression of BAG3 encoding nucleic acid and/or BAG3 protein. Therefore, a person of ordinary skill in the art would recognize that the applicant was not in possession of the genus, “an agent,” that modulates expression or amount of BAG3 encoding nucleic, BAG3 protein or BAG3 peptide at the time of filing. Claims 5 and 6 are not directed to limiting the genus of “an agent” and therefore do not cure this deficiency.
Claims 1-6, 11-15, 19, 21-23, 25-26, and 28 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 reducing TNFR1-associated signaling and associated sterile inflammation in myocardial cells or cardiac tissue characterized by BAG3 haploinsufficiency or reduced BAG3 expression, using adenovirus-mediated overexpression of wild-type BAG3, does not reasonably provide enablement for a method of reducing, inhibiting, or decreasing TNF signaling in any patient and in any tissue or organ system by administering any agent, or BAG3 encoding nucleic acid, BAG3 protein or BAG3 peptide, including any functional BAG3 variant or fragment. 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 use the invention commensurate in scope with these claims.
A consideration of the factors set forth in In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988), establishes that undue experimentation would be required to practice the full scope of the claims.
(A) The breadth of the claims: The claims are very broad in two distinct respects. First, “BAG3 encoding nucleic acid, BAG3 protein or BAG3 peptide,” as read in light of the specification, encompasses full-length BAG3, functional variants, modified forms, and fragments/peptides without defined sequences, mutation limits, or required structural features, and “agent” encompasses any molecule, chemical entity, composition, drug, therapeutic agent, or biological agent capable of preventing, ameliorating, or treating a disease or other medical condition. Second, the claims encompass reduction of TNF signaling or inflammation in a patient generally, while dependent claims 4 and 5 recite a broad collection of disparate organ systems including pulmonary, cardiovascular, central nervous system, skeletal, gastrointestinal, hepatic, renal, and pancreatic tissues, and claim 6 recites chronic inflammatory disease, chronic inflammatory demyelinating polyneuropathy, primary immune thrombocytopenia, geriatric anorexia, gut inflammation, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lupus, rheumatoid arthritis, chronic myocarditis, chronic myocarditis after Covid 19 infection, psoriasis, psoriatic arthritis or ankylosing spondylitis. The claimed scope therefore extends far beyond the disclosed BAG3 +/- myocardial model and adenoviral overexpression of wild-type BAG3.
(B) The nature of the invention: The application addresses the problem that reduced BAG3 expression is associated with harmful inflammation, abnormal apoptosis, and mitochondrial dysfunction. The specification says BAG3 haploinsufficiency shifts cells toward TNF-linked, caspase-mediated cell death and disrupts mitochondrial calcium homeostasis. It also states that these changes may contribute to tissue injury and disease progression in the heart and other organs. The inventors aim to provide a way to restore BAG3 function or level to reduce these effects. The solution is to administer BAG3 itself, a BAG3-encoding nucleic acid, or a BAG3-expressing vector so the patient has more functional BAG3. The disclosed mechanism is that BAG3 helps restrain TNF signaling, caspase-8 and caspase-3 activation, and PARP1-linked inflammatory cell death. BAG3 also supports mitochondrial protein interactions and calcium handling, which helps maintain mitochondrial membrane potential and cell survival. In short, restoring BAG3 is presented as a way to dampen inflammation by stabilizing apoptosis and mitochondria-related signaling.
(C) The state of the prior art: The prior art recognized BAG3 as a multifunctional protein associated with protein quality control, autophagy, apoptosis, cardiomyocyte maintenance, and disease phenotypes arising from BAG3 insufficiency such as myofibrillar myopathy and cardiomyopathy, and that BAG3 performs its various functions and interacts with various other proteins through different functional domains. see Knezevic T, et al., (BAG3: a new player in the heart failure paradigm. Heart Fail Rev. 2015 Jul;20(4):423-34, in IDS, refer sections: abstract; introduction; BAG3 mutants, myofibrillar myopathy and dilated cardiomyopathy; and autophagy and apoptosis).
(D) The level of one of ordinary skill: A person of ordinary skill in the art would be a PhD trained scientist with several years postdoctoral experience in molecular biology, protein engineering, viral-vector design, and cellular signaling assays. While this level of skill would permit construction and testing of particular BAG3 constructs, it would not provide the ability to predict from the entire claimed sequence and delivery breadth, which BAG3 forms and delivery conditions would achieve reduced TNF signaling in each of the claimed tissues and disease states.
(E) The level of predictability in the art: The state of the art did not provide a general structure-function rule that any BAG3 nucleic acid, protein, peptide, variant, or fragment would retain the relevant functions in order to reduce TNF signaling across the varied tissues and inflammatory diseases encompassed in the claims, see Knezevic, Structure–function relationships of BAG3. The prior art further recognized that amino-acid mutations are often destabilizing and that effects on protein fitness are conditional and difficult to predict. Predicting the functional consequences of even single nucleotide or amino-acid changes remained a substantial challenge. See pg. 602 of Tokuriki et al, 2009, Current Opinion in Structural Biology. 19: 596-604 and pg. 18 of Bhattacharya et al, 2017. Plos One. 12(3): e0171355, pages 1-22 as printed. The need for empirical evaluation is particularly significant because BAG3 acts through multiple domains to interact with multiple different binding partners and intracellular environments rather than through one simple and universally transferable biochemical activity, see Knezevic, Structure–function relationships of BAG3.
(F) The amount of direction provided by the inventor: The specification provides direction for evaluating BAG3 haploinsufficiency-associated alterations in myocardial cells and reports adenoviral wild-type BAG3 overexpression in BAG3+/- cardiac myocytes. It does not provide a teaching that identifies which BAG3 fragments, peptides, substitutions, deletions, or combinations thereof retain the activity required to reduce TNAF signaling. The specification also does not identify a common structural feature that correlates with reduction of TNF signaling, a domain map defining permissible modification sites, fragment boundaries that retain the claimed functional activity, or predictive screening results for selecting functional BAG3 variants or peptides. Nor does it provide a treatment protocol showing reduction of TNF signaling across the claimed organ systems or inflammatory conditions.
(G) The existence of working examples: The working examples are concentrated in BAG3+/- myocardial tissue/cells and demonstrates associations between BAG3 deficiency and TNF-receptor/inflammasome-related changes. The adenoviral rescue experiment demonstrates restoration of mitochondrial calcium-uniporter activity by overexpressed wild-type BAG3 in the cardiac BAG3+/- model, rather than reduction of TNF signaling across the full scope of the claims. There are no representative working examples provided for BAG3 protein therapy, BAG3 peptide therapy, substantially mutated BAG3 variants, or defined functional BAG3 fragments in the broad non-cardiac tissues or inflammatory conditions claimed.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure: To identify embodiments throughout the claimed scope, the skilled artisan would need to engage in undue experimentation by generating and testing numerous BAG3 encoding nucleic acids, protein variants, fragments, and peptides for expression, folding, stability, localization, protein interactions, and retention of relevant BAG3 activity. The skilled artisan would further need to evaluate each selected embodiment for reduction of TNF signaling in the specific intended tissue and inflammatory disease context. The necessary experiments would be especially extensive for non-cardiac tissues and diseases, because the disclosure supplies no reasonable correlation between its myocardial BAG3-haloinsufficieny findings and TNF-signaling reduction in the other claimed contexts. The experimentation is therefore undue.
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.
Claims 6, 14-15, and 26 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 6 recites the limitation “the inflammation or inflammatory response” in line 2. There is insufficient antecedent basis for this limitation in the claim. Specifically, parent claim 2 only refers to inflammation and not an inflammatory response, and thus does not provide antecedent basis for the alternative in the dependent claims directed to “the … inflammatory response”.
In claim 14, lines 3-4, “hepatitis virus vectors” is indefinite because it is unclear how “a viral vector” (singular) of parent claim 13 can comprise multiple vectors.
Claims 26 recites the limitation “the patient or human” in line 2. There is insufficient antecedent basis for this limitation in the claim. Specifically, parent claim 1 only refers to a patient, and not a human, and thus does not provide antecedent basis for the alternative in the dependent claim directed to “the … human”.
The remaining claim(s) included in the rejection are dependent claims that depend from one of the claims rejected above, and encompass the same indefinite subject matter.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 2 and 5-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Turco MC (US20190010221A1).
Regarding claim 2, Turco teaches a method for treating a patient suffering from, or, at risk of developing inflammation comprising: administering to the patient an amount of an agent that modulates expression or amount of BCL2-associated athanogene 3 (BAG3) encoding nucleic acid, BAG3 protein or BAG3 peptide thereby treating inflammation (see abstract: “BAG3 antibodies as a medicament, in particular for use in the treatment of pancreatic tumors or other pathologies of an immune, inflammatory, neoplastic and/or degenerative nature;” and see [0014]: “treatment with any of the anti-BAG3 antibodies described in patent application no. WO03/055908 able to inhibit, specifically, the activity of soluble BAG3 protein (i.e. extra-cellular) on macrophages, that are considered the target cells, proves particularly effective in the treatment of those pathologies characterized by the activation of macrophages, such as neoplastic diseases and diseases of an inflammatory, immune, or degenerative nature.”).
Regarding claims 5-6, Turco teaches wherein the inflammation or inflammatory response affects the pulmonary system, lung, cardiovascular system, central nervous system, bone, skeletal joints, skeletal muscle, gastrointestinal system, stomach, small intestine, large intestine, liver, kidney or pancreas (see [0047]: ““inflammatory diseases can be chosen from diseases related to inflammation of the skin, nerves, bones, blood vessels, and connective tissues, and more preferably, psoriasis, arthritis, neuritis, connectivitis,”), and wherein the inflammation or inflammatory response comprises chronic inflammatory disease, chronic inflammatory demyelinating polyneuropathy, primary immune thrombocytopenia, geriatric anorexia, gut inflammation, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lupus, rheumatoid arthritis, chronic myocarditis, chronic myocarditis after Covid 19 infection, psoriasis, psoriatic arthritis or ankylosing spondylitis (see [0048]: “can be chosen from autoimmune diseases such as rheumatic diseases, connective tissue diseases, neuromuscular diseases, endocrine diseases, gastrointestinal diseases, haematologic diseases, skin diseases, and vasculitis, and more preferably, rheumatoid arthritis, multiple sclerosis, connectivitis, lupus erythematosus, endometriosis, and ulcerative colitis.”).
Claims 2-3 and 5-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Feldman AM, (WO2019237002A1).
Regarding claims 2 and 5-6, Feldman teaches a method for treating a patient suffering from, or, at risk of developing inflammation comprising: administering to the patient an amount of an agent that modulates expression or amount of BCL2-associated athanogene 3 (BAG3) encoding nucleic acid, BAG3 protein or BAG3 peptide thereby treating inflammation, (see claim 1: “A method of … treating a patient having cardiac disease, comprising: identifying in a patient sample, at least one Bcl2-associated anthanogene 3 (BAG3) genetic variant as compared to a control BAG3 nucleic acid sequence, wherein detection of certain genetic variants are predictive of whether an increase in BAG3 levels is therapeutic for the patient, and administering to the patient identified as having such a genetic variant, a therapeutically effective amount of an agent wherein the agent modulates expression or amount of BAG3 molecules, proteins or peptides thereof in a target cell or tissue, as compared to a normal control.”), and wherein the inflammation or inflammatory response affects the pulmonary system, lung, cardiovascular system, central nervous system, bone, skeletal joints, skeletal muscle, gastrointestinal system, stomach, small intestine, large intestine, liver, kidney or pancreas (see [0033]: “herein, “cardiac disease” refers to any type of heart disease including … myocarditis…,” which is an inflammatory cardiac disease), and wherein the inflammation or inflammatory response comprises chronic inflammatory disease, chronic inflammatory demyelinating polyneuropathy, primary immune thrombocytopenia, geriatric anorexia, gut inflammation, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lupus, rheumatoid arthritis, chronic myocarditis, chronic myocarditis after Covid 19 infection, psoriasis, psoriatic arthritis or ankylosing spondylitis (see again [0033] “…myocarditis,” which can be a chronic inflammatory heart disease for example as claimed after COVID 19).
Regarding claim 3, Feldman’s agent, for example, may comprise wild-type BAG3 protein, which would increase BAG3 levels, thereby treating myocarditis by reducing, inhibiting, or decreasing inflammation.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-4, 11-15, 19, 21-23, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Feldman AM (WO2015117010A2, herein “Temple”) in view of Liao Q, et al., (The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines. FEBS Lett 2001; 503: 151–157), Chiappetta G, et al., (The antiapoptotic protein BAG3 is expressed in thyroid carcinomas and modulates apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand. J Clin Endocrinol Metab. 2007 Mar;92(3):1159-63), and Webster JD, et al., (The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues. Front Cell Dev Biol. 2020 May 21;8:365).
Regarding claim 1, Temple teaches administering to a patient an amount of BCL2-associated athanogene 3 (BAG3) encoding nucleic acid, BAG3 protein or BAG3 peptide, see claims 1-2 and 7.
Regarding claims 3 and 4, Temple teaches “a method of preventing or treating a subject at risk of or suffering from a cardiac disease or disorder comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one agent which modulates, expression of BAG3, or a BAG3 polynucleotide or polypeptide. In preferred embodiments the cardiac disease and/or disorder is heart failure,” see [0187]. Temple further teaches “cardiac disease refers to any type of heart disease including… myocarditis…,” which is an inflammatory disease. Feldman further contemplates that the agents not only are useful for treating inflammatory cardiac diseases but also that “the agents modulate the expression of Bcl-2 associated anthanogene-3 {BAG 3) in patients suffering from or at risk of developing diseases or disorders associated with molecules or pathways associated with BAG3,” and that “[e]xamples of such diseases or disorders associated comprise: cardiac diseases or disorders, skeletal muscle diseases or disorders, multiple sclerosis, senile plaques, cerebral amyloid angiopathy, atherosclerosis, glioblastoma, amyloid deposition, neurodegenerative diseases, neurofibrillary tangles, dementia, choriocarcinoma, astrocytoma, amyloidosis, hyperlipidemia, neurodegeneration, neoplastic transformation, prostate cancer, atherosclerotic plaque, obstruction, AIDS, metastasis, myocardial infarction, pulmonary fibrosis, necrosis, shock, melanoma, colorectal carcinoma, genetic susceptibility, psoriasis, cancer, inflammation, glioma, carcinoma, breast cancer, neuropathology, tumors, prostate carcinoma, vascular diseases, cell damage, brain tumors, Non- small cell lung carcinomas (NSCLCs), hypercholesterolemia. Examples of skeletal muscle diseases include, primary (genetic) diseases of muscle (e.g., muscular dystrophies and congenital myopathies, metabolic myopathies); acquired diseases (e.g. myositis, toxic myopathy); secondary diseases of muscle (e.g. neurogenic atrophy, atrophy from chronic pulmonary, heart, kidney disease, HIV/AIDs, cancer, sarcopenia and the like,” see [0201].
Regarding claim 11, Temple further teaches “wherein the agent comprises an expression vector expressing a BAG3 protein or active fragments thereof, oligonucleotides or combinations thereof,” see claim 2.
Regarding claim 12 and 20, Temple further teaches “wherein the expression vector further comprises a promoter, the promoter comprising an inducible promoter, a constitutive promoter, bicistronic promoter or tissue specific promoter,” see claim 3.
Regarding claim 13, Temple further teaches “wherein the expression vector comprises a viral vector, cardiotropic vector, plasmid, or a yeast vector,” see claim 4.
Regarding claim 14, Temple further teaches “wherein a cardiotropic vector comprises an adenovirus vector, an adeno-associated virus vector (AAV), a coxsackie virus vector, cytomegalovirus vector, Epstein- Barr virus vector, parvovirus vector, or hepatitis virus vectors,” see claim 5.
Regarding claim 15, Temple further teaches “the vector is an adenovirus-associated viral vector (AAV), for example, AAV9,” see [085].
Regarding claim 22, Temple further teaches wherein the promoter confers expression in the pulmonary system, lung, cardiovascular system, central nervous system, bone, skeletal joints, skeletal muscle, gastrointestinal system, stomach, small intestine, large intestine, liver, kidney or pancreas, see [081-082].
Regarding claim 23, Temple further teaches that the “AAV vectors can have one or more of the AAV wild-type genes deleted in whole or part, preferably the rep and/or cap genes, but retain functional flanking ITR sequences,” see [085].
Regarding claim 25, Temple further teaches “the subject is a human,” see [088].
Temple does not teach administering to a patient an amount of BCL2-associated athanogene 3 (BAG3) encoding nucleic acid, BAG3 protein or BAG3 peptide to reduce, inhibit or decrease TNF signaling.
Liao teaches “increased BAG-3 expression might contribute to a resistance to apoptosis via several mechanisms: 1. BAG-3 contains a conserved approximately 45-amino acid region, termed the BAG domain The BAG domain specifically binds and stimulates the ATPase activity of Hsp70/Hsc70 and modulates the function of these molecular chaperones. The homologous BAG-1 protein, which interacts with Hsp70/Hsc70, causes a wide variety of cellular effects, including increased resistance to apoptosis, enhanced cell proliferation, tumor cell migration and metastasis… Hsp70 also protects tumor cells from TNF-α cytotoxicity even in the absence of heat treatment and various other stresses. Therefore, it can be hypothesized that BAG-3 might also provide cytoprotective functions through its effects on Hsp70/Hsc70. 2. BAG-3 exhibits sequence similarity to SODD (BAG-4), which is a recently identified molecule that is reported to block spontaneous self-association of TNF-α receptors, and thereby prevent apoptosis and NFκB induction. While there is no experimental evidence that BAG-3 functions to block signaling of TNF-α members at the receptor level, it is intriguing to speculate that enhanced expression of BAG-3 could contribute to the observed resistance of pancreatic cancer cells to members of the TNF-α family, especially considering that there have been no convincing molecular explanations for this phenomenon.” See Discussion. Thus, Liao provided a motivation to investigate BAG3 as a modulator of TNF-family signaling.
Chiappetta teaches “Cell apoptotic response to TRAIL was significantly (P < 0.0195) enhanced in cultures treated with BAG3-specific, but not control scrambled, siRNA,” and that “accordingly, caspase 8 activation, an event involved in TRAIL-triggered apoptosis pathway, was amplified in bag3 siRNA-treated cells,” see results. Thus, Chiappetta experimentally demonstrated that BAG3 levels actually modulate cellular responsiveness to a TNF-family death ligand.
Webster teaches “[t]umor necrosis factor alpha (TNF; TNFα) is a critical regulator of immune responses in healthy organisms and in disease,” and that “[d]isruption of these signaling events can disturb the balance and the composition of signaling complexes, potentially resulting in severe inflammatory diseases,” see abstract. Webster further teaches that “TNF inhibition is efficacious in the treatment of many inflammatory disease,” see RIP1 Inhibitors for Treatment of TNF Mediated Inflammatory Diseases.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to employ the methods of Temple to reduce TNF signaling in a patient. A PHOSITA would have been motivated to employ the methods of Temple to reduce TNF signaling because reducing TNF signaling was known to provide therapeutic benefits by decreasing TNF-mediated apoptosis, inflammation, and other deleterious cellular effects. A PHOSITA would have had a reasonable expectation of success because Liao identified BAG3 as a potential modulator of TNF-family responses, and Chiappetta demonstrated that altering BAG3 levels modulates cellular responses to a TNF-family ligand, including caspase-activation.
Claims 19 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Feldman AM (WO2015117010A2, herein “Temple”) in view of Liao Q, et al., (The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines. FEBS Lett 2001; 503: 151–157), Chiappetta G, et al., (The antiapoptotic protein BAG3 is expressed in thyroid carcinomas and modulates apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand. J Clin Endocrinol Metab. 2007 Mar;92(3):1159-63), and Webster JD, et al., (The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues. Front Cell Dev Biol. 2020 May 21;8:365) as applied to claim 1 above, and further in view of Feldman AM, (WO2019237002A1).
The teachings of Temple, Liao, Chiappetta, and Webster are incorporated herein by reference to the 103 rejection above.
Temple, Liao, Chiappetta, and Webster do not teach wherein the patient expresses lower than normal levels of BAG3 in a tissue or organ or does not detectably express or produce functional BAG3, or wherein the patient or human has a mutation in their endogenous BAG3 polynucleotide or polypeptide.
Feldman teaches patients express lower than normal levels of BAG3 and that patients have mutation in their endogenous BAG3, see claim set [0065].
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to [1]. A PHOSITA would have been motivated because restoring BAG3 levels or supplying wild type BAG3 would ameliorate the effects of deficient BAG3. A PHOSITA would have had a reasonable expectation of success because Temple and Feldman already establish administering BAG3 to such patients.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Feldman AM (WO2015117010A2, herein “Temple”) in view of Liao Q, et al., (The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines. FEBS Lett 2001; 503: 151–157), Chiappetta G, et al., (The antiapoptotic protein BAG3 is expressed in thyroid carcinomas and modulates apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand. J Clin Endocrinol Metab. 2007 Mar;92(3):1159-63), and Webster JD, et al., (The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues. Front Cell Dev Biol. 2020 May 21;8:365) as applied to claim 13 above, and further in view of Gradinaru V, et al., (WO2020068990A1).
The teachings of Temple, Liao, Chiappetta, and Webster are incorporated herein by reference to the 103 rejection above.
Temple, Liao, Chiappetta, and Webster do not teach wherein the viral vector is administered or formulated at a dose from about 0.1×1012 vector genomes (vg)/weight of the patient in kilograms (vg/kg) to about 1.0×1014 vg/kg.
Gradinaru teaches viral vectors administered at a dose from about 0.1×1012 vector genomes (vg)/weight of the patient in kilograms (vg/kg) to about 1.0×1014 vg/kg, see [00213].
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to provide the viral vector of Feldman at a dose from about 0.1×1012 vector genomes (vg)/weight of the patient in kilograms (vg/kg) to about 1.0×1014 vg/kg. A PHOSITA would have been motivated because to optimize dosage for human patients. A PHOSITA would have had a reasonable expectation of success because this dosing regimen was standard practice in the art.
Claims 2-3 and 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over Cao YL, et al., (A role of BAG3 in regulating SNCA/α-synuclein clearance via selective macroautophagy. Neurobiol Aging. 2017 Dec;60:104-115) in view of Pajares M, et al., (Inflammation in Parkinson's Disease: Mechanisms and Therapeutic Implications. Cells. 2020 Jul 14;9(7):1687) and Sandoval IM, et al., (Gene Therapy to Modulate Alpha-Synuclein in Synucleinopathies. J Parkinsons Dis. 2021;11(s2):S189-S197).
Claims 2 and 3 each encompass a method for treating a patient suffering from inflammation comprising administering an agent that increases an amount of BAG3 encoding nucleic acid, thereby treating inflammation. The specification describes the method as useful for treating Parkinson’s disease (PD).
Regarding claims 2-3 and 5, Cao teaches that “Parkinson’s disease (PD) is the most common neurodegenerative movement disorder” (i.e., a central nervous system (CNS) disorder) “and characterized by the death of dopaminergic neurons and formation of Lewy bodies in the substantia nigra pars compacta. Although its etiology remains elusive, many studies demonstrate that both genetic and environmental factors result in the formation of inclusion body, which is mainly composed of misfolded SNCA/α-synuclein and other ubiquitinated proteins” (page 104). Cao reports that overexpression of BAG3, using a BAG3-encoding plasmid (page 106), reduced accumulation of SNCA (alpha-synuclein) in cells (page 114). Cao teaches that “BAG3 attenuates SNCA accumulation via enhancing macroautophagy activity” (page 114). Cao further teaches “our findings reveal that BAG3 may become a therapeutic target for PD [Parkinson’s disease] treatment” (page 115).
Cao does not expressly teach administering a BAG-encoding nucleic acid to a patient with PD or that PD patients experience chronic inflammation.
Pajares teaches that “inflammation in Parkinson’s disease (PD) encompasses central and peripheral inflammation. The “gut–brain axis” hypothesis in PD holds that alterations in the gut microbiota may favor α-Syn aggregation and are responsible for an inflammatory response in the periphery, which includes increased cytokine levels and activated T cells. Aggregated α-Syn is suggested to spread from the periphery to the brain through the vagus nerve in a prion-like manner. Once in the brain, proteinopathy together with other triggering factors (mitochondrial impairment, ROS, etc.) will sustain central inflammation in a vicious circle between dying dopaminergic neurons, glial cells and activated endothelium, further aggravated by infiltrating peripheral immune cells.” See Figure 2. Pajares concludes that “chronic inflammation can directly or indirectly contribute to the etiology and progression of PD,” and that “due to the central role of inflammation in PD, immunomodulatory therapies become prime targets for research,” see concluding remarks.
Sandoval, in a review titled “Gene Therapy to Modulate Alpha-Synuclein in Synucleinopathies” teaches that “point mutations and gene multiplications of SNCA alter the aggregation potential of α -Syn and cause PD in a dose-dependent manner … thus, indisputably linking α -Syn to the disease process” (page S189) and “[b]ased on the assumption that α-Syn pathology is a cause and not a consequence of disease, anti-Synuclein strategies have emerged as the indisputable disease-modifying therapeutic strategy” (page S190). Sandoval further teaches that “CNS gene therapy has made great strides, and PD has a rich history utilizing gene therapy, with 25 trials currently listed on clinicaltrials.gov involving PD, albeit none have been aimed at modulating α-Syn” (page S194).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to take the BAG3-encoding nucleic acid taught by Cao and administer it to a patient with Parkinson’s disease for gene therapeutic treatment of PD as taught by Sandoval and Pajares. The person of ordinary skill in the art would have been motivated to make such a change in order to treat Parkinson’s disease, and would have had a reasonable expectation of success in view of the results observed by Cao that BAG3 overexpression can reduce alpha-synuclein levels. This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007). The modified method of treatment obvious over the teachings of Cao in view of Pajares and Sandoval meets the limitations of claims 2-3 and 5-6.
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 1-6, 11-15, 19, 21-23, 25-26, and 28 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-19 of U.S. Patent No. US11236389B2 in view of Liao Q, et al., (The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines. FEBS Lett 2001; 503: 151–157), Chiappetta G, et al., (The antiapoptotic protein BAG3 is expressed in thyroid carcinomas and modulates apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand. J Clin Endocrinol Metab. 2007 Mar;92(3):1159-63), and Webster JD, et al., (The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues. Front Cell Dev Biol. 2020 May 21;8:365).
The claims are not patentably distinct because ‘389 claims methods of administering BAG3 nucleic acid, BAG3 protein, or an expression vector comprising a BAG3 polynucleotide to a human patient to increase BAG3 expression, including use of viral vectors, AAV vectors, cardiac-specific promoters, and AAV ITRs. The instant claims similarly recite administration of BAG3 nucleic acid, protein, peptide, or expression vectors to a human patient, including substantially overlapping vector, promoter, and ITR limitations, but further recite reducing TNF signaling or inflammation. As discussed in the corresponding 35 U.S.C. 103 rejection, Liao provides motivation to increase BAG3 to modulate TNF-family signaling, Chiappetta demonstrates that modulation of BAG3 levels alters cellular responsiveness to a TNF-family ligand, and Webster teaches the benefit of reducing TNF signaling. Accordingly, the additional TNF-signaling and inflammatory limitations do not render the instant claims patentably distinct from the claims of ‘389.
Claims 1-6, 11-15, 19, 21-23, 25-26, and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-6, and 11-33 of copending Application No. 17971477 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference application and the instant claims recite nearly identical overlapping methods of administrating BAG3 nucleic acid, BAG3 protein, or BAG3 peptide to treat or reduce TNF signaling or inflammation, including substantially identical overlapping expression vectors, promoters, viral vectors, dosing, tissues, and human patients.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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