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 .
Priority
This is a National Stage Entry under 35 U.S.C. 371 of International Patent Application
No. PCT/CN2022/135269, filed November 30, 2022. This application also claims priority to Chinese application CN202111167024.2, filed on October 01, 2021.
Drawings
The drawings are objected to because 3, 4, 6, 7, 8, and 12 is not of sufficient quality. The labels for the X and Y axis and the legend of Figure 3, 4, 6, 7, 8, and 12 are illegible. 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
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:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. Figure 10 contains sequences that are not accompanied with sequences identifiers (i.e., “SEQ ID NO:X).
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, 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.
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
The file must be submitted in bytes not kilobytes.
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 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.
Claim Objections
Claims 1 – 5 and 12 are objected to because of the following informalities:
Claims 1 – 5 and 12 recite “SEQ ID NO.” The claims should recite “SEQ ID NO:”.
Claims 2 – 5 recite “The recombinant fusion protein from the HR region of novel coronavirus S2 protein of claim.” The claims should recite “The recombinant fusion protein of claim…”
Appropriate correction is required.
Claim Interpretation
For examination purposes, “an antigen detection reagent” of claim 7 is understood as any reagent that can bind to antigens including antigen binding poly peptides and antibodies.
Claims 7, 8, 10, 11, and 13 were interpreted as product-by-process claims. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) See MPEP 2113.
"The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature" than when a product is claimed in the conventional fashion. In re Fessmann, 489 F.2d 742, 744, 180 USPQ 324, 326 (CCPA 1974). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing an nonobvious difference between the claimed product and the prior art product. In re Marosi, 710 F.2d 799, 803, 218 USPQ 289, 292-33 (Fed. Cir. 1983).
"[T]he lack of physical description in a product-by-process claim makes determination of the patentability of the claim more difficult, since in spite of the fact that the claim may recite only process limitations, it is the patentability of the product claimed and not of the recited process steps which must be established. We are therefore of the opinion that when the prior art discloses a product which reasonably appears to be either identical with or only slightly different than a product claimed in a product-by-process claim, a rejection based alternatively on either section 102 or section 103 of the statute is eminently fair and acceptable. As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith." In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972).
Here, claims 7, 8, 10, 11, and 13 are drawn to products that made using the heptad-repeat (HR) fusion proteins. The claims are not drawn to a method for producing an antibody, antigen-binding protein, vaccine, and/or neutralizing antibody. As such, for purposes of applying prior art, claims 7, 8, 11, and 13 were broadly interpreted herein encompass any antibody that bind and/or neutralize SARS-CoV-2. Regarding claim 10, the HR fusion protein of claim 1 is used as an immunogen. Thus, claim 10 was broadly interpreted as any product produced in response to the HR fusion protein of claim 1, which includes antibodies.
Claim Rejections - 35 USC § 112 - Indefiniteness
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 1 – 13 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.
Claims 1 – 5, and 12 recite the phrase “shown in SEQ ID NO…” It is not clear whether the Applicants intend this limitation to read on only the full sequence, a partial sequence, or at least the full sequence. For purposes of compact prosecution and applying prior art, claims 1 – 5, and 12 were interpreted herein as “comprising the amino acid sequence of SEQ ID NO…” and “comprising the nucleotide sequence of SEQ ID NO…” respectively. The dependent claims and do not add additional clarity and, therefore, are also indefinite.
Claims 1 – 13 recite the phrase “novel coronavirus”. It is not clear whether the Applicants intend to limit the claims to any novel coronavirus discovered. For purposes of examination, “novel coronavirus” was understood herein to mean the SARS-CoV-2 virus consistent with the Specification.
Claims 6 and 9 recite the phrase “skeleton vector”. It is not clear whether the Applicants intend this limitation to read on a vector comprising just encoding a fusion protein or at least a fusion protein. For purposes of examination, “skeleton vector” was understood herein to mean a vector comprising a nucleic acid encoding at least a fusion protein.
Claim 7 recites the phrase “an antigen detection reagent and/or a medicament”. It is not clear whether the Applicants intend this limitation to read on an antibody or antigen-binding domain. It is not clear as whether the Applicants intend “medicament” to read on a pharmaceutical composition or a protein that can bind to an antigen. For purposes of examination, “an antigen detection reagent and/or a medicament” was understood herein to mean an antibody or antigen-binding protein.
Claim Rejections - 35 USC § 112 – Written Description
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 7, 8, 11, and 13 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 written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See, e.g., Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010); University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) at 1406; Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ("[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[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.' (internal quotation marks omitted).").
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). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568,43 USPQ2d l398, 1406 (Fed. Cir. 1997). The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to “visualize or recognize the identity of the members of the genus.”
Claims 7, 8, 11, and 13 broadly encompass an antibody directed towards SARS-CoV-2 (See claim interpretation). There is not sufficient description of the structural features that must be retained to establish a functional relationship with respect to binding to a SARS-CoV-2 virus, and, in some embodiments, neutralizing a SARS-CoV-2 virus.
The Specification has failed to sufficiently describe the structural features that must be retained by members of the claimed genus as to establish a structure-function relationship with respect to the ability of the antigen-binding polypeptide or antibody to bind to its target protein such as a component of SARS-CoV-2. The claims define the protein based on it does—not what it is. Additionally, the Specification has failed to sufficiently describe the structural features that must be retained by members of the claimed genus as to establish a structure-function relationship with respect to the binding to and, in some embodiments, neutralizing the target protein resulting in a broad, vague, and nebulous genus of proteins that may satisfy the claim limitations.
While the instant claims are drawn to a genus that comprises innumerable number of antibodies or antigen binding polypeptides, the Specification has not reduced to practice any antigen-binding peptide or antibody. The Specifications and Drawings merely point to two possible antibodies that are only defined by the names “HR121 antibody” and “HR212 antibody” as well as antiserum against the HR121 and HR212 proteins (Figures 6, 7, 8, 13; ¶0162, 0169, 0174). However, this is not representative of the extremely large genus of antibodies or antigen binding polypeptides claimed. Furthermore, the CDRs required for the function of binding to and/or neutralizing a SARS-CoV-2 virus are not identified in the Specifications nor the Drawings, adding to the broad, vague, and nebulous genus of proteins that may satisfy the claim limitations.
The data generated for the select antibodies described in the Specification and Drawings cannot reasonably be extrapolated and applied to support possession of the entire claimed genus of antibodies and antigen-binding polypeptides thereof because no there is no defined portion of the amino acid sequence that accounts for the structure amongst the claimed genus. As in Ariad, 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 that one has invented a genus and not just a species. “A patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.” Brenner v. Manson, 383 U.S. 519, 536 (1966).
Moreover, Rudikoff et al (PNAS, 1982, hereinafter, “Rudikoff”) teaches that highly similar antibody structures do not result in predictable function. Rudikoff teaches the CDR plays a key role in the target affinity of an antibody, showing that even a single amino acid alteration in the CDR can result in loss of antigen-binding function (Section: Implications for Generation of Diversity). Because the properties and function of an antibody are highly dependent upon the amino acid sequences and exact combination of CDRs, wherein, even one amino acid difference in a CDR region leads to different functional properties, different conformations of CDR sequences would result in antibodies or antigen-binding fragments having different properties.
Furthermore, Einav et al (bioRxiv, 2020, hereinafter, “Einav”) teaches models of antibody mixtures through simulation. Einav teaches that even though models can be used to account for to help predict the activity of antibody mixtures, it can be “difficult to predict how antibodies will behave when mixed together, even after each has been independently characterized” (Abstract). Thus, when taken with the teachings of Rudikoff and Einav, one of skill in the art would readily appreciate that mere knowledge of structure alone cannot serve as the basis to describe members of the genus that have the recited function because a single antibody’s or antigen-binding polypeptide’s structure is unpredictable.
In the absence of a representative number of examples, the Specification must at least
describe the structural features that are required for the claimed function, in this case binding to and, in some embodiments, neutralizing a target protein. However, as discussed above, the Specification fails to describe any substantive structural limitations as to establish a structure-function relationship with respect to epitope binding activity. The Specification also fails to describe which regions, domains, etc. of the antibody sequences must be retained in order to bind to the target protein such as SARS-CoV-2. Instead, Applicant merely offers a cursory statement that any antibody or antigen-binding poly peptide that binds to an epitope will work.
Accordingly, the claims as currently written are not adequately described and one of skill in the art would readily appreciate that Applicant was not in possession of the claimed genus at the time of filing.
Claim Rejections - 35 USC § 112 – Scope of Enablement
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 7, 8, 10, and 11 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 reducing the risk of SARS-CoV-2 viral infections by administering a heptad-repeat (HR) fusion protein, does not reasonably provide enablement for preventing a SARS-CoV-2 infection in the absolute sense. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to:
• (A) The breadth of the claims;
• (B) The nature of the invention;
• (C) The state of the prior art;
• (D) The level of one of ordinary skill;
• (E) The level of predictability in the art;
• (F) The amount of direction provided by the inventor;
• (G) The existence of working examples; and
• (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Here, the instant claims are broadly drawn to a method for the prevention of SARS-CoV-2 infection within a subject by administering a vaccine, antibody, and/or vector comprising a HR fusion protein. In regard for prevention of a SARS-CoV-2 infection, it is noted that the term “preventing” was interpreted in an absolute sense to mean to always keep something from happening or arising.
The claims are not enabled based on the fact that not all SARS-CoV-2 infection are prevented by the recited SARS-CoV-2 HR fusion protein as recited in the claims. The level of skill in the art is high and would include, e.g., Ph.D. level scientists.
The art establishes COVID 19 vaccines such as mRNA-based ones encoding a S2 protein are not 100% effecting in preventing SARS-CoV-2 infection as evidenced by Polack et al (NEJM, 2020, 10.1056/NEJMoa2034577, hereinafter, “Polack”) (Abstract). Polack teaches a large-scale trial of the vaccine with a 95% efficacy in reducing the risk of SARS-CoV-2 infection (Abstract). Furthermore, Polack teaches that this protective effect was observed in all demographic groups (Abstract). While Polack teaches the vaccine is effective, it is not able to prevent 100% of all cases (Abstract).
Furthermore, Walensky et al (US20240124529A1, hereinafter, “Walensky”) teaches cross-linked peptides that are using for interfering with and inhibiting coronavirus infections, including SARS-CoV-2 (Abstract). Walensky teaches that while several fusion proteins comprised of HR1 and HR 2 were effective at reducing infections in Vero E6 cells, none were able to completely reduce infection of SARS-CoV-2 within cells (Figure 27 – 32).
Thus, when taken with the teachings of Polack and Walensky, one of skill in the art would readily appreciate that a composition comprising HR fusion proteins cannot serve as the basis to describe the method to have the recited function of preventing SARS-CoV-2 infection.
In view of the evidence discussed above, there is a reasonable expectation that a composition comprising a SARS-CoV-2 HR fusion protein would not prevent an infection from SARS-CoV-2 in the absolute sense.
The specification only exemplifies a reduction of the viral load of SARS-COV 2 in lung tissue after the administration of HR121 but not a total absence of SARS-CoV-2 viral load (Figure 9). Importantly, the specification does not recite any working examples of preventing a SARS-CoV-2 infection within a subject. Likewise, the Specification fails to disclose which dosages, administration routes, and administration routines must be must be retained to reduce the likelihood of SARS-CoV-2 infection. However, this is not sufficient to describe the claimed method because such methods can vary widely in efficacy.
In view of the foregoing, a vast quantity of experimentation, including expansive clinical trials, would be needed to use the invention based on the content of the disclosure.
Taken together, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 7, 8, 10, 11, and 13 is rejected under 35 U.S.C. 101 because the claimed inventions are directed to a judicial exception without significantly more. This judicial exception is not integrated into a practical application, and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below. See MPEP § 2106 for patent subject matter eligibility analysis.
Claims 7, 8, 10, 11, and 13 are drawn to an antibody (See Claim Interpretation for Claim 7) which is a composition of matter and a statutory category of invention (Step 1- YES).
Claims 7, 8, 10, 11, and 13 are drawn to an antibody produced in response to the introduction of SARS-CoV-2 HR proteins.
Thus, claims 7, 8, 10, 11, and 13 are drawn to any protein with a domain that binds to a portion of SARS-CoV-2 HR proteins, which is a domain of the naturally occurring viral spike protein. A domain of a naturally occurring protein does not exhibit a markedly different characteristic from the naturally occurring protein. Indeed, Li et al (Cellular & Molecular Immunology, 2020, 10.1038/s41423-020-00523-5, hereinafter, “Li”) teaches several antibodies that were isolated from COVID-19 convalescent individuals that target the SARS-CoV-2 HR proteins (¶3, Figure 1A, Figure 1B). As such, claims 7, 8, 10, 11, and 13 recites a judicial exception in the form of a natural phenomenon (product of nature) (Step 2A, Prong 1- YES).
The crux of the claimed invention is an antibody or antigen detection reagent, which reads on an antibody, produced in response to SARS-CoV-2 HR proteins. The instant claims do not recite any additional elements that integrate this judicial exception into a practical application, such as specific treatment or prophylaxis. Rather, the instant claims are limited to the judicial expectation. As such, the instant claims do not recite additional elements that integrate the judicial exception into a practical application (Step 2A, Prong 2- NO).
As detailed above and in the 35 U.S.C. § 103 rejections below, the claimed polypeptides of SEQ ID NOs: 3 is a naturally occurring viral polypeptide. The instant claims do not recite any additional elements that amount to significantly more than the judicial exception (Step 2B- NO).
Accordingly, claims 7, 8, 10, 11, and 13 do not constitute patent eligible subject matter under 35 U.S.C. § 101.
Claim Rejections - 35 USC §§ 102/103
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 7, 8, 10, 11, and 13 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Li et al (Cellular & Molecular Immunology, 2020, 10.1038/s41423-020-00523-5, hereinafter, “Li”).
As discussed above, claims 7, 8, 10, 11, and 13 were interpreted herein as product-by-process claims, which broadly encompass any antibody or antigen-binding fragment that bind and/or neutralize SARS-CoV-2.
Li discloses the exploration of antibody responses to the S protein of SARS-CoV-2 at an epitope resolution (¶1). Li discloses the characterization of several antibodies that were isolated from COVID-19 convalescent individuals that target the SARS-CoV-2 HR proteins (¶3, Figure 1A, Figure 1B). Li discloses that many antibodies target HR region of the S protein at higher rates than other portions of the S protein (Figure 1B). Li also discloses that the neutralizing antibodies that target portions adjacent to HR2 may interfere with the helical bundle formation just as those antibodies targeting HR2 would (¶7).
In the alterative, it would have been prima facie obvious before the effective filing date of the claimed invention to have isolated the antibodies taught by Li to detect SARS-CoV-2, treat a SARS-CoV-2 infection, or reduce the risk of SARS-CoV-2 infection. One of ordinary skill in the art would have reasonable expectation of success in isolating and using the antibodies that target the HR region of SARS-CoV-2 taught by Li to detect SARS-CoV-2, treat a SARS-CoV-2 infection, or reduce the risk of SARS-CoV-2 infection given that antibodies directed towards the HR region are well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, Li anticipates the claimed invention or, in the alternative, renders the claimed invention prima facie obvious.
Claim(s) 1 – 6, 9, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Walensky et al (US20240124529A1, hereinafter, “Walensky”) in view of Ni et al (BIuochem Biophys Res Commun, 2005, 10.1016/j.bbrc.2005.02.117, hereinafter, “Ni”), Sivaramakrishnan et al (PNAS, 2011, 10.1073/pnas.1116066108, hereinafter, “Sivaramakrishnan”), and Nagamune et al (Nano Converg, 2017, 10.1186/s40580-017-0103-4, hereinafter, “Nagamune”).
Walensky teaches cross-linked peptides that are useful for interfering with and inhibiting coronavirus infections, including SARS-CoV-2 (Abstract). Walensky also teaches that these peptides can be used for treating infections (Abstract). Walensky teaches that SARS-CoV-2 S protein undergoes a conformational change resulting in a formation of heptad-repeat (HR) bundles that brings the host and viral membranes together (¶¶ 0005, 0104).
[AltContent: textbox (Qy 1 TQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3 TQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFG 62
Qy 61 AISSVLNDILSRLDKVE
INSTANT CLAIM SEQ ID NO: 1 ALIGNMENT )][AltContent: textbox (Qy 1 DVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKY
||||||||||||||||||||||||||||||||||||||||||||
Db 87 DVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKY
INSTANT CLAIM SEQ ID NO: 2 ALIGNMENT )]Regarding claims 1 and 12, Walensky teaches the exact HR1 and HR2 sequences of instant claims 1 and 12, arranged in a HR1-Linker-HR2-Linker-H1 arrangement. The HR1 of Walensky has a 100% sequence identity with SEQ ID 1 (reproduced below, “Qy” is SEQ ID NO: 1, “Db” is Walensky). Additionally, Walensky teaches a HR2 sequence with 100% sequence identity to SEQ ID NO: 2 (reproduced below, “Qy” is SEQ ID NO: 2, “Db” is Walensky). However, Walensky does not teach the exact linkers of claims 1 and 12.
However, Ni teaches that SARS-CoV enters a cell by first binding of the S1 domain of the spike protein to a receptor, followed by conformational changes of the spike protein S2 domain, resulting in the formation of HR bundles (Abstract). Ni teaches recombinant proteins containing either two HR1 and one HR2 peptides (HR121) or two HR2 and one HR1 peptides (HR212) can be used to as inhibitors of SARS-CoV entry (Abstract). Furthermore, Ni teaches that these peptides can be linked through linker sequences to form the recombinant protein (Figure 1).
[AltContent: textbox (Qy 1 GGSGG 5
|||||
Db 1 GGSGG 5
INSTANT CLAIM SEQ ID NO: 3 ALIGNMENT )][AltContent: textbox (Qy 1 SGGRGG 6
||||||
Db 1 SGGRGG 6
INSTANT CLAIM SEQ ID NO: 4 ALIGNMENT )]Regarding claims 1 and 12, Ni teaches the exact linkers of SEQ ID NOs: 3 and 4 that are used to link multiple HR peptides (Figure 1, Figure 1 caption, sequence alignment reproduced below, “Qy” is SEQ ID NOs: 3 and 4, “Db” is Ni).
[AltContent: textbox (RESULT 2
PCT-US21-20940-263
(NOTE: this sequence has 1 duplicate in the database searched)
Sequence 263, PC/TUS2120940
GENERAL INFORMATION
APPLICANT: DANA-FARBER CANCER INSTITUTE, INC.
TITLE OF INVENTION: ANTIVIRAL STRUCTURALLY-STABILIZED SARS-COV-2 PEPTIDES AND USES
TITLE OF INVENTION: THEREOF
FILE REFERENCE: 00530.0401WO1 / 2823.W01WO
CURRENT APPLICATION NUMBER: PCT/US21,20940
CURRENT FILING DATE: 2021-03-04
PRIOR APPLICATION NUMBER: 62/985,100
PRIOR FILING DATE: 2020-03-04
Query Match 94.9%; Score 957; Length 358;
Best Local Similarity 97.6%;
Matches 207; Conservative 0; Mismatches 1; Indels 4; Gaps 4;
Qy 1 TQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3 TQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFG 62
Qy 61 AISSVLNDILSRLDKVE-GGSGG-DVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLI 118
||||||||||||||||| || || ||||||||||||||||||||||||||||||||||||
Db 63 AISSVLNDILSRLDKVESGGRGGPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLI 122
Qy 119 DLQELGKYSGGRGG-TQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNA 177
|||||||| ||||| |||||||||||||||||||||||||||||||||||||||||||||
Db 123 DLQELGKY-GGRGGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNA 181
Qy 178 QALNTLVKQLSSNFGAISSVLNDILSRLDKVE 209
||||||||||||||||||||||||||||||||
Db 182 QALNTLVKQLSSNFGAISSVLNDILSRLDKVE 213
INSTANT CLAIM SEQ ID NO: 5 ALIGNMENT )]Regarding claim 2, Walensky teaches a HR121 protein that has 97.2% sequence identity to SEQ ID NO: 5 with 5 amino acid difference with regard to the linkers (reproduced below, “Qy” is SEQ ID NO: 5, “Db” is Walensky). Substituting the linkers with those taught by NI would result in 100% sequence identity.
Regarding claim 3, Walensky teaches a HR212 protein that has 97.2% sequence identity to SEQ ID NO: 6 with 5 amino acid difference with regard to the linkers (reproduced below, “Qy” is SEQ ID NO: 6, “Db” is Walensky). Substituting the linkers with those taught by NI would [AltContent: textbox (RESULT 2
PCT-US21-20940-263
(NOTE: this sequence has 1 duplicate in the database searched)
Sequence 263, PC/TUS2120940
GENERAL INFORMATION
APPLICANT: DANA-FARBER CANCER INSTITUTE, INC.
TITLE OF INVENTION: ANTIVIRAL STRUCTURALLY-STABILIZED SARS-COV-2 PEPTIDES AND USES
TITLE OF INVENTION: THEREOF
FILE REFERENCE: 00530.0401WO1 / 2823.W01WO
CURRENT APPLICATION NUMBER: PCT/US21,20940
CURRENT FILING DATE: 2021-03-04
PRIOR APPLICATION NUMBER: 62/985,100
PRIOR FILING DATE: 2020-03-04
Qy 1 DVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYSGGRGG-TQNVLYENQ 59
|||||||||||||||||||||||||||||||||||||||||||| ||||| |||||||||
Db 87 DVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKY-GGRGGVTQNVLYENQ 145
Qy 60 KLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDI 119
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 146 KLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDI 205
Qy 120 LSRLDKVE-GGSGG-DVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKY 176
|||||||| || || ||||||||||||||||||||||||||||||||||||||||||||
Db 206 LSRLDKVESGGRGGPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKY 264
INSTANT CLAIM SEQ ID NO: 6 ALIGNMENT )]result in 100% sequence identity.
Regarding claims 4 and 5, a nucleic acid sequence encoding the fusion protein of HR1 and HR2, as taught by Walensky, with the linkers taught by Ni would result in a nucleic acid sequence with 100% sequence identity to SEQ ID NOs: 7 and 8 (reproduced below, “Qy” is SEQ ID NOs: 7 and 8, “Db” is Walensky and Ni with the linkers taught by Ni in bold).
[AltContent: textbox (Qy 1 ACACAGAATGTTCTCTATGAGAACCAAAAATTGATTGCCAACCAATTTAATAGTGCTATT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ACACAGAATGTTCTCTATGAGAACCAAAAATTGATTGCCAACCAATTTAATAGTGCTATT 60
Qy 61 GGCAAAATTCAAGACTCACTTTCTTCCACAGCAAGTGCACTTGGAAAACTTCAAGATGTG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GGCAAAATTCAAGACTCACTTTCTTCCACAGCAAGTGCACTTGGAAAACTTCAAGATGTG 120
Qy 121 GTCAACCAAAATGCACAAGCTTTAAACACGCTTGTTAAACAACTTAGCTCCAATTTTGGT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GTCAACCAAAATGCACAAGCTTTAAACACGCTTGTTAAACAACTTAGCTCCAATTTTGGT 180
Qy 181 GCAATTTCAAGTGTTTTAAATGATATCCTTTCACGTCTTGACAAAGTTGAGGGAGGAAGC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GCAATTTCAAGTGTTTTAAATGATATCCTTTCACGTCTTGACAAAGTTGAGGGAGGAAGC 240
Qy 241 GGAGGAGATGTTGATTTAGGTGACATCTCTGGCATTAATGCTTCAGTTGTAAACATTCAA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GGAGGAGATGTTGATTTAGGTGACATCTCTGGCATTAATGCTTCAGTTGTAAACATTCAA 300
Qy 301 AAAGAAATTGACCGCCTCAATGAGGTTGCCAAGAATTTAAATGAATCTCTCATCGATCTC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 AAAGAAATTGACCGCCTCAATGAGGTTGCCAAGAATTTAAATGAATCTCTCATCGATCTC 360
Qy 361 CAAGAACTTGGAAAGTATAGCGGAGGAAGAGGAGGAACACAGAATGTTCTCTATGAGAAC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 CAAGAACTTGGAAAGTATAGCGGAGGAAGAGGAGGAACACAGAATGTTCTCTATGAGAAC 420
Qy 421 CAAAAATTGATTGCCAACCAATTTAATAGTGCTATTGGCAAAATTCAAGACTCACTTTCT 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 CAAAAATTGATTGCCAACCAATTTAATAGTGCTATTGGCAAAATTCAAGACTCACTTTCT 480
Qy 481 TCCACAGCAAGTGCACTTGGAAAACTTCAAGATGTGGTCAACCAAAATGCACAAGCTTTA 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 TCCACAGCAAGTGCACTTGGAAAACTTCAAGATGTGGTCAACCAAAATGCACAAGCTTTA 540
Qy 541 AACACGCTTGTTAAACAACTTAGCTCCAATTTTGGTGCAATTTCAAGTGTTTTAAATGAT 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 AACACGCTTGTTAAACAACTTAGCTCCAATTTTGGTGCAATTTCAAGTGTTTTAAATGAT 600
Qy 601 ATCCTTTCACGTCTTGACAAAGTTGAGTAA 630
||||||||||||||||||||||||||||||
Db 601 ATCCTTTCACGTCTTGACAAAGTTGAGTAA 630
INSTANT CLAIM SEQ ID NO: 7 ALIGNMENT )]
[AltContent: textbox (Qy 1 GATGTTGATTTAGGTGACATCTCTGGCATTAATGCTTCAGTTGTAAACATTCAAAAAGAA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GATGTTGATTTAGGTGACATCTCTGGCATTAATGCTTCAGTTGTAAACATTCAAAAAGAA 60
Qy 61 ATTGACCGCCTCAATGAGGTTGCCAAGAATTTAAATGAATCTCTCATCGATCTCCAAGAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ATTGACCGCCTCAATGAGGTTGCCAAGAATTTAAATGAATCTCTCATCGATCTCCAAGAA 120
Qy 121 CTTGGAAAGTATAGCGGAGGAAGAGGAGGAACACAGAATGTTCTCTATGAGAACCAAAAA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 CTTGGAAAGTATAGCGGAGGAAGAGGAGGAACACAGAATGTTCTCTATGAGAACCAAAAA 180
Qy 181 TTGATTGCCAACCAATTTAATAGTGCTATTGGCAAAATTCAAGACTCACTTTCTTCCACA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TTGATTGCCAACCAATTTAATAGTGCTATTGGCAAAATTCAAGACTCACTTTCTTCCACA 240
Qy 241 GCAAGTGCACTTGGAAAACTTCAAGATGTGGTCAACCAAAATGCACAAGCTTTAAACACG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GCAAGTGCACTTGGAAAACTTCAAGATGTGGTCAACCAAAATGCACAAGCTTTAAACACG 300
Qy 301 CTTGTTAAACAACTTAGCTCCAATTTTGGTGCAATTTCAAGTGTTTTAAATGATATCCTT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 CTTGTTAAACAACTTAGCTCCAATTTTGGTGCAATTTCAAGTGTTTTAAATGATATCCTT 360
Qy 361 TCACGTCTTGACAAAGTTGAGGGAGGAAGCGGAGGAGATGTTGATTTAGGTGACATCTCT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 TCACGTCTTGACAAAGTTGAGGGAGGAAGCGGAGGAGATGTTGATTTAGGTGACATCTCT 420
Qy 421 GGCATTAATGCTTCAGTTGTAAACATTCAAAAAGAAATTGACCGCCTCAATGAGGTTGCC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GGCATTAATGCTTCAGTTGTAAACATTCAAAAAGAAATTGACCGCCTCAATGAGGTTGCC 480
Qy 481 AAGAATTTAAATGAATCTCTCATCGATCTCCAAGAACTTGGAAAGTATTAA 531
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 AAGAATTTAAATGAATCTCTCATCGATCTCCAAGAACTTGGAAAGTATTAA 531
INSTANT CLAIM SEQ ID NO: 8 ALIGNMENT )]
Regarding claim 6, Ni teaches a pGEX-6P-1 vector encoding a HR121 fusion protein (Section: Gene construction).
Regarding claim 9, Ni teaches a pGEX-6P-1 vector encoding a HR212 fusion protein (Section: Gene construction).
Walensky and Ni considered to be analogous to the claim invention because they teach HR fusion proteins that are directed towards coronaviruses. Walensky teaches the exact HR1 and HR2 sequences of instant claims 1 and 12, arranged in a HR1-Linker-HR2-Linker-H1 or HR2-Linker-HR1-Linker-H2 arrangement. Ni teaches the exact linkers of SEQ ID NOs: 3 and 4 that are used to link multiple HR peptides (Figure 1, Figure 1 caption).
It would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal linker for use in for the HR fusion protein taught by Walensky to maximize the biological activity of the fusion protein with a reasonable expectation of success.
Identifying the optimal linker for fusion proteins through trial and error is routine experimentation for engineering proteins. Sivaramakrishnan teaches identifying ideal linkers to control inter-protein interaction of a fusion protein, stating protein activity “changing the specific linker sequence by trial and error” (Section: Engineering FRET Biosensors). The routine optimization of linkers is ubiquitous in laboratories and has led to a push to computationally determine the optimal linker sequence as taught by Nagamune (Section: 3.5.2.7 Rational algorithms and software for designing linker sequences and structures). Nagamune reviews the state of protein engineering, including the engineering of fusion proteins. Nagmune evidences that “[m]ost current approaches to linker selection and design processes for fusion proteins are still largely dependent on experience and intuition” (Section: 3.5.2.7 Rational algorithms and software for designing linker sequences and structures).
Here, the instant claim encompasses selecting a linker sequence for the fusion protein and as such is readily obtained by routine optimization.
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to optimize the HR fusion protein taught by Walensky with the linkers taught by Ni because doing so would ensure proper expression of the fusion protein. One of ordinary skill in the art would have reasonable expectation of success in selecting a linker given that these linkers in the context of HR fusion proteins are well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Conclusion
NO CLAIMS ARE ALLOWED
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/DANYAL HASSAN ALAM/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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