DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant's election with traverse of Group I (Claims 1-17 and 20) and the following species elections:
An oncolytic virus comprising an M protein with SEQ ID NO: 5 and amino acid substitutions M51R, V221F, and S226R relative to SEQ ID NO: 1; and G protein with SEQ ID NO: 17 and amino acid substitutions V53I, A141V, D172Y, K217E, D232G, V331A, V371E, G436D, T438S, F453L, T471I, and Y487H relative to SEQ ID NO: 2;
VSV and the Indiana MuddSummer subtype; and
The oncolytic virus does not comprise or express an exogenous target protein
in the reply filed on 21 July 2026 is acknowledged. The traversal is on the ground(s) that the subject matter of all claims and inventions are sufficiently related since a thorough search for the subject matter of any one group of claims or inventions would encompass a search for the remaining and thus there is no serious search burden. This is not found persuasive because the groups of inventions were found to be independent and distinct as the process of making can be used to make another and materially different product AND there would be a serious search burden for the reasons stated previously. See sections 3-4 of the Requirement for Restriction/Election mailed 01 June 2026. Applicant provides no rebuttal to the findings of the restriction. Furthermore, their argument appears to be applying unity of invention standard to the instant case which is application of an incorrect legal standard as the instant case is a 111.
The requirement is still deemed proper and is therefore made FINAL.
Claims 13, 15-19, and 21-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 21 July 2026.
Priority
3. The Instant Application is a continuation of PCT/CN2022/104525 filed 08 July 2022, which claims priority to foreign application CN202110798531.X filed 14 July 2021.
Receipt is acknowledged of certified copies of papers required by 35 CFR 1.55. Should Applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CRF 41.154(b) and 41.202(e). Therefore, the effective filing date for purposes of applying prior art is 08 July 2022.
Failure to provide a certified translation may result in no benefit being accorded for the non-English translation.
Claim Status
4. Claims 13, 15-19, and 21-25 are withdrawn.
Claims 1-12, 14, and 20 are under consideration.
Information Disclosure Statement
5. The information disclosure statements (IDS) submitted on 15 October 2025, 10 June 2025, and 19 January 2024 were filed before the mailing date of the Non-Final Office Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
6. 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.
Drawings
7. The drawings are objected to under 37 CFR 1.83(a) because they fail to show the wild-type virus in Figure 12 as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
8. Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
9. Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, 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.
See the primers in ¶ [0197]-[0198], [0204]-[0205].
Specification
10. The use of the terms “Opti-MEM” and “Plus Reagent” (¶ [0212]) and “TRIzol” and “LightCycler” (¶ [0242]), which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Note that these are merely examples and all improper uses of trademarks in the specification should be identified by Applicant and properly addressed.
Claim Objections
11. Claims 10-12 and 20 are objected to because of the following informalities:
Regarding claims 10-12, “comprises” should be “is” for clarity.
Regarding claim 20, the comma before “and” should be removed.
Appropriate correction is required.
Claim Interpretation
12. Regarding the claim language of “having amino acid substitutions…” in claims 1 and 4-5, “having” is being interpreted as “comprising”. See MPEP 2111.03.IV.
Claim Rejections - 35 USC § 112(b)
13. 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.
14. Claims 1-12, 14, and 20 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.
Regarding claims 1, 3-4, and 9, “comprises an amino acid sequence as shown in” can be interpreted as the full-length sequence of the sequence identifier or a fragment thereof. Therefore, there are multiple structural interpretations and this renders the claims indefinite.
Claims 2-12, 14, and 20, which depend on claim 1, are similarly rejected.
Claims 4-12 and 14, which depend on claims 2-3, are similarly rejected.
Claim 1-2 and 4-8 are rejected for claiming the limitation of amino acid positions within a protein sequence without providing an appropriate frame of reference for said sequence. Said frame of reference can be provided by referencing a sequence disclosed within the application (i.e. a sequence with a SEQ ID NO: identifier). Currently, it is unclear where position 1 is. For example, the M protein positions could be interpreted as relative to the beginning of SEQ ID NO: 1 or there could be a signal peptide before SEQ ID NO: 1 that would change the relative position. Additionally, the presence of fragments would also make the positions unclear.
Claims 2-12, 14, and 20, which depend on claim 1, are similarly rejected.
Claims 4-12 and 14, which depend on claim 2, are similarly rejected.
Claim 9, which depends on claim 8, is similarly rejected.
See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.").
Claim Rejections - 35 USC § 112(a) – Written Description
15. 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.
16. Claims 1-12, 14, and 20 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.
The claims above are drawn to an oncolytic virus with M and G proteins that have “an amino acid sequence” with amino acid substitutions at undefined positions. Additionally, the G protein has “at least one amino acid substitution” and thus it could have an amino acid substitution at every single position. However, the specification only shows working examples for the mutated M protein with SEQ ID NOs: 3-5 and the mutated G protein with SEQ ID NOs: 6-28 and does not contemplate any fragments or additional mutations. Thus, it is clear that the breadth of the recited peptides in the claims far overreaches Applicant’s contribution as disclosed in the specification and so this rejection is made. One of ordinary skill in this art cannot conclude that Applicant was in possession of just any mutation of the M and G proteins. An enormous breadth of mutated proteins are thus not represented by Applicant at all. Even if the prior art is aware of additional M and G proteins, the totality of known mutated or truncated M or G proteins would not be representative of the entire genus for the reasons discussed below.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
MPEP § 2163 states that 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, 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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the peptide inhibitors can have any sequence, one must describe a sufficient variety of species to reflect the variation within the genus. However, one of skill in this art cannot envision the structure of any other peptides with the required function other than the few species provided by Applicant and the prior art. Therefore, since only a few species are provided to represent the genus, the claims encompassing the same clearly fail the written description requirement.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members.
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). Since there are only a few mutated M and G proteins taught by Applicant, and mutated polypeptides would vary in structure, there is no correlation between structure and function between the members of the recited or any peptide genus. Additional mutated polypeptides could read on any and all combinations of amino acids. Thus, since there is no correlation between structure and peptide function across the entire genus, functional language should not be used to define a peptide genus. Rather, structure should be used, including the core peptide sequence required for said function.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since the genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus.
Overall, at the time the invention was made, the level of skill for preparing peptides and then selecting those peptides with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify peptides with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010). Absent the conserved structure provided by a core inhibitory peptide sequence, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what any peptide with a particular set of functional properties would look like structurally.
Since no mutations are taught in the specification of the recited genus above, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe such a massive genus. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe said genus.
Owed to the variation among the peptides of the genus as broadly as currently claimed, it is very difficult to provide adequate representation of the functionally defined peptide genus. There is unlikely to be any structure (subsequence) shared by the entire genus. If there is a subsequence common to all or some of Applicant’s species, then the claims should recite that as part of the peptide genus to provide adequate representation of the actual disclosed/possessed group. Also, the disclosure of one group of highly related peptides does not guide one of skill to the next peptide of the genus with said function. Finding a another said peptide would require mutation and it is well-known in this art that mutation of peptides leads to specific function loss.
The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess, 1990, J. Cell Bio., 111: 2129-2138). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar, 1988, Molecular and Cellular Biology, 8: 1247-1252). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (1991, PNAS, 88: 2658-2662) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (2000, Immunity, 13: 475-484) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through mutagenesis. Importantly, binding can still occur after mutation, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (1997, J. Biol. Chem., 272: 21201-21206) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
Thus, while applicant has described a few species within the genus recited, and the art may provide more, each genus is very large and would encompass peptide structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the peptide structures encompassed by the claimed/recited genus only defined by function. Any future peptide may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the entire recited genus of peptides. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite that the peptide genus must comprise the core peptide responsible for the recited function as this would define the structure/function relationship of the species Applicant possesses.
Claim Rejections - 35 USC § 112(a) – Enablement
17. In making a determination as to whether an application has met the requirements forenablement under 35 U.S.C. 112 ¶ 1, the courts have put forth a series of factors. See, In reWands, 8 USPQ2d 1400, at 1404 (CAFC 1988). The factors considered include: (1) the breadth of the claims, (2) the nature of the invention, (3) the relative skill of those in the art, (4) the presence or absence of working examples, (5) the amount of direction or guidance provided, (6) the state of the prior art, (7) the level of predictability in the art, and (8) the quantity of experimentation necessary.
18. Claims 1-12, 14, and 20 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 defined and tested protein shown to be functional, does not reasonably provide enablement for any and all possible mutant variants of the M and G proteins. 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 the invention commensurate in scope with these claims.
The claims are drawn to an oncolytic virus with M and G proteins, that have amino acid substitutions. These proteins can be the full-length peptide or truncations thereof.
The nature of the invention is an oncolytic virus.
The level of skill of one of ordinary skill in this art is high.
The specification provides working examples for the mutated M protein with SEQ ID NOs: 3-5 and the mutated G protein with SEQ ID NOs: 6-28 but does not contemplate any fragments or additional mutations.
The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, conservative replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess, 1990, J. Cell Bio., 111: 2129-2138). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar, 1988, Mol. Cell. Biol., 8: 1247-1252). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (1991, PNAS, 88: 2658-2662) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (2000, Immunity, 13: 475-484) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (1997, J. Biol. Chem., 272(43): 27155-27159) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (1998, Nat. Genet., 18: 150-154) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (2009, Hum. Mol. Genet., 18(18): 3353-3364) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (1997, J. Biol. Chem., 272: 21201-21206) who teaches that receptor binding does not predict agonist or antagonist activity (Page 21205, Column 2, ¶ first full, first sentence).
With respect to the use of peptides in the treatment of a disease such as cancer, the state of the art at the time of filing was such that it was unpredictable whether or not a peptide would function therapeutically. Their functionality depends, in part, on whether or not they reach their intended target in a sufficient quantity as to cause a therapeutic effect. Mendoza (2005, Arch. Immunol. Ther. Exp., 53: 47-60) teaches that peptides derived from larger molecules that are important modulators of apoptosis are frequently becoming leads for the development of anticancer therapeutics (Page 48, Column 2, ¶ first partial). However, they also state that natural peptides have low bioavailability and short half-life in the mammalian circulation system, while synthetic peptides have potential cytotoxicities (Page 57, Column 1, ¶ last full). Due to these characteristics, systematic testing in in vivo as well as in vitro settings must be done rigorously to verify peptide applications in the clinic (Page 57, Column 1, ¶ last full). Taken together, barring experimental evidence, no peptide can merely be assumed to function in the treatment of a disease, for example cancer, in vivo just because it functions as an inhibitor in vitro.
Since the art teaches that it is unpredictable whether or not peptide variants of known inhibitors will function as such and it is also unpredictable that even a known inhibitory peptide that functions in vitro will function in vivo, it would also be unpredictable to that the polypeptide variants will retain their original function or function as desired. Since the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of instant claims as broadly as they are currently claimed.
Claim Rejections - 35 USC § 103
19. 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.
20. 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.
21. Claims 1-12, 14, and 20 are rejected under 35 U.S.C. 103 as being obvious over Janelle (July 2011, J. Virol., 85(13): 6513-6520) in view of Qin (WO 2019184459 A1; Published 03 October 2019; See English translation) and Kim (US 20210106632 A1; Published 15 April 2021, Filed 28 September 2018).
Regarding claims 1-12, Janelle teaches “VSV G mutants represent promising oncolytic viruses” (Page 6519, ¶ 3), wherein “the MM51R mutant shows the same D216G substitution in its G protein as mutants G5 and G6” (Page 6515, ¶ 1). Therefore, Janelle teaches that an oncolytic virus can comprise VGV mutated M and G proteins. Janelle does not teach the exact amino acid substitutions recited or the MuddSummer subtype of VSV.
However, Qin teaches an oncolytic virus vaccine that has a modified matrix (M) protein (Abstract). This modified protein has M51R, V221F, and G226R mutations, resulting in SEQ ID NO: 5 (Page 5, ¶ 5). SEQ ID NO: 5 of Qin has a 100% match to SEQ ID NO: 5 of the Instant Application:
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415
630
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Qin also teaches that SEQ ID NO: 5 is from the VSV MuddSummer strain (Page 20).
Kim teaches “a recombinant plasma membrane-based vesicle, and more specifically to a recombinant plasma membrane-based vesicle comprising a VSV-G mutated protein” (Abstract), wherein the vesicle is for treating cancer (¶ [0001]) and the wild-type VSV-G protein is SEQ ID NO: 1 (¶ [0110]). SEQ ID NO: 1 of Kim has a 100% match to SEQ ID NO: 17 of the Instant Application:
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707
651
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Using the VSV G protein from Kim will result in a G protein with amino acid substitutions V53I, A141V, D172Y, K217E, D232G, V331A, V371E, G436D, T438S, F453L, T471I, and Y487H relative to SEQ ID NO: 2, which is equivalent to SEQ ID NO: 17. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). “Products of identical chemical composition can not have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990)
Therefore, it would have been obvious to one of ordinary skill before the filing date to take the oncolytic VSV of Janelle and further substitute the MuddSummer VSV M protein from Qin and the wild-type VSV G protein from Kim to arrive at the oncolytic virus, as claimed. Substituting the proteins for known functional variants is obvious. A wild-type G protein as described by Kim would be equally obvious to use as a mutated one that has been shown to work. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.). A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02).
Regarding claim 14, Janelle teaches “If VSV G mutants are to be considered for oncolytic virotherapy, they should first be able to replicate efficiently. VSV G mutants were therefore tested for their ability to replicate on L929 cells (Fig. 1). Despite mutations in the surface glycoprotein, all mutants replicated as efficiently as wild-type VSV regardless of the multiplicity of infection (MOI). We also tested replication of the M protein mutant MM51R and observed that it could also establish a productive infection, although this was reduced by 100-fold compared to that of G mutants.” (Page 6515, ¶ 2). Qin further teaches that the composition can comprise an isolated recombinant oncolytic baculovirus having a nucleic acid fragment encoding the modified matrix protein (Page 5, ¶ 7) and Kim further teaches SEQ ID NO: 2, which is a nucleic acid sequence of a polynucleotide encoding the wild-type VSV-G protein of SEQ ID NO: 1 (¶ [0111]).
Since Janelle already teaches these VSV mutants having both M and G mutated proteins, it would be equally obvious for the oncolytic virus to comprise a nucleic acid molecule that encodes for both the M and G proteins. This is made further obvious by the fact that the oncolytic virus of Janelle was able to replicate, indicating the presence of nucleic acids as they are required in order for the virus to replicate inside the cells.
Regarding claim 20, Qin further teaches that the oncolytic virus vaccine can be administered with a suitable carrier, such as physiological saline or other pharmaceutically suitable buffer (Page 8, last ¶).
Double Patenting
22. 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.
23. Claims 1-12, 14, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-15, 36-37, 39-40, and 48 of copending Application No. 18/785,273 in view of Janelle (July 2011, J. Virol., 85(13): 6513-6520), Qin (WO 2019184459 A1; Published 03 October 2019), and Kim (US 20210106632 A1; Published 15 April 2021, Filed 28 September 2018).
Although the claims at issue are not identical, they are not patentably distinct from each other because SEQ ID NO: 12 of ‘273 has a 98.2% match to SEQ ID NO: 5 of the Instant Application:
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Note that the substitutions of the Instant Application are present. Claim 7 of ‘273 recites that the M protein comprises SEQ ID NO: 12. SEQ ID NO: 12 reads on an embodiment of claims 1-6 and 8 of ‘273.
SEQ ID NO: 43 of ‘273 has a 100% match to SEQ ID NO: 17 of the Instant Application:
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The full sequence alignment has been omitted due to length. Claim 13 of ‘273 recites that the G protein comprises SEQ ID NO: 43. SEQ ID NO: 43 also reads on an embodiment of claims 8-12 of ‘273.
Claims 36-37 of ‘273 recite that the oncolytic virus is VSV and the Indian MuddSummer subtype, respectively. Claim 39 of ‘273 recites that the oncolytic virus comprises a nucleic acid molecule that can comprise the M protein with substitutions and/or the G protein with amino acid substitutions. Claim 40 of ‘273 recites that the nucleic acid molecule of claim 39 comprises a nucleic acid sequence encoding the foreign nucleic acid, target gene, or protein. Claim 48 of ‘273 recites a pharmaceutical composition comprising the oncolytic virus of claim 1 and optionally a pharmaceutically acceptable carrier.
In addition, the combination of Janelle, Qin, and Kim render obvious claims 1-12, 14, and 20 surpa. The addition of claims 1, 3-15, 36-37, 39-40, and 48 of ‘273 only further support this obviousness and thus the prior art combined with said claims renders the instant claims above obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
24. No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA E LY whose telephone number is (571)272-5169. The examiner can normally be reached Monday - Thursday, 8:00 am - 5:00 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at (571) 270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KRISTINA E. LY/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
Prosecution Insights