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 .
DETAILED ACTION
Claims 1-7 and 9-22 are currently pending and under prosecution.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The specification has embedded hyperlinks at least on pages 7 and 8, last paragraphs on both pages.
The disclosure is objected to because of the following informalities: The specification refers to “SEQ ID NO: 10”. SEQ ID NO: 10 is less than 4 amino acids “FND” and sequences less than 4 amino acids are prohibited to be named “SEQ ID NO: XX” under ST.26. Applicant should amend the specification to replace all relevant SEQ ID NO: 10 with the actual sequence “FND”.
Appropriate correction is required.
Specification/Abstract
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because the abstract recites terms that are not clear and concise or phrases which can be implied, such as inter alia. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claim 3 is objected to because of the following informalities: Claim 3 recites “The antibody or antigen-binding fragment thereof of claim 1, further comprising a heavy chain constant domain comprises an amino acid sequence…” The claim is grammatically incorrect, and should recite “…further comprising a heavy chain constant domain which comprises an amino acid sequence….” Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-7 and 9-22 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. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn an isolated antibody or an antigen-binding fragment thereof that specifically binds to SARS-CoV-2 spike protein receptor-binding domain (RBD), comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR H1 comprising an amino acid sequence of at least 70% identity to SEQ ID NO: 1, a CDR H2 comprising an amino acid sequence of at least 70% identity to in SEQ ID NO: 2 and/or a CDR H3 comprising an amino acid sequence of at least 70% identity to SEQ ID NO: 3; and wherein said light chain variable domain comprises a CDR L1 comprising an amino acid sequence of at least 70% identity to SEQ ID NO: 9, a CDR L2 comprising an amino acid sequence of at least 70% identity to SEQ ID NO: 10, and/or a CDR L3 comprising an amino acid sequence of at least 70% identity to SEQ ID NO: 11.
Dependent claim 2 recites the heavy chain variable domain comprises an amino acid sequence of at least 70% identity to SEQ ID NO: 4 and/or the light chain variable domain comprises an amino acid sequence of at least 70% identity to SEQ ID NO: 12.
Dependent claim 3 recites further comprising a heavy chain constant domain comprises an amino acid sequence of at least 70% identity to SEQ ID NO: 5 and/or a light chain constant domain comprises an amino acid sequence of at least 70% identity to SEQ ID NO: 13.
Dependent claim 4 recites that the antibody a heavy chain full-length sequence having at least 70% identity to SEQ ID NO: 6 or 8 and/or a light chain full-length sequence having at least 70% identity to SEQ ID NO: 14 or 15.
Thus, the claims provide only a partial structure of the isolated antibody or antigen binding fragment thereof that binds to SARS-CoV-2 spike protein receptor-binding domain (RBD), wherein they comprise only 70% of the instantly claimed sequence, and can have up to 30% sequence discrepancy anywhere, including in the sequences critical to binding function. Furthermore, the claims recite that the heavy chain and light chain variable domains may comprise only one of the CDR regions. Thus, the claims encompass a genus of antibodies having either 30% sequence discrepancy from the disclosed CDR SEQ ID Nos, or only one of the CDR sequences from the heavy and light chain sequences with each CDR sequence having up to 30% sequence.
The instant specification discloses one example of the instantly claimed antibody, the MR92250 antibody, which comprises the following sequences (also listed on Table 1 of the disclosed specification):
Heavy chain CDRH 1-2-3: SEQ ID NOS: 1, 2, 3
Heavy chain variable domain: SEQ ID NO: 4
Heavy chain constant domain: SEQ ID NO: 5
Heavy chain full-length sequence: SEQ ID NO: 6
Light chain CDR L 1- 2- 3: SEQ ID NOs: 10 (FND) – 11-12
Light chain variable domain: SEQ ID NO: 12
Light chain constant domain: SEQ ID NO: 13
Light chain full length sequence: SEQ ID NO: 14
Thus, the specification fails to disclose any other representative variants comprising less than 100% that function as an antibody that binds to the SARS-CoV-2 spike protein RBD.
The structure activity relationship of the CDR antigen binding regions that recognizes the SARS-CoV-2 spike protein receptor-binding domain (RBD) is not known and the binding epitopes cannot be predicted based on the antibody sequences. The SARS-CoV-2 spike protein RBD antigen provides no information concerning the sequence/structure of antibodies that bind the given antigen.
By the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4.
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156 page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Benchmarking B cell epitope prediction: Underperformance of existing methods, Protein Science (2005), 14:246–248 pg. 246) . 3D structural analyses of antibody-epitope binding highlighting that the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al.,3D-Epitope-Explorer (3DEX): Localization of Conformational Epitopes within Three-Dimensional Structures of Proteins, Wiley Interscience, 2005 42–44, 60596, page 879).
Furthermore, changes in amino acid structures, particularly in CDR regions, can have impacts on antigen binding that are unpredictable. Rabia et al (Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility. Biochemical engineering journal, 137, 365–374, 2018) and Vajdos et al (Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis. Journal of molecular biology, 320(2), 415–428, 2022) teaches that changes to CDRs are unpredictable in terms of affinity, specificity, and solubility, (see Rabia whole documents), and teaches that even minute changes to the CDR region can impact binding affinities. (see Figure 2, effects of CDR mutations on binding affinity), respectively. Rudikoff et al (Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1979-83) teaches that single amino acid substitutions alter antigen-binding specificity. [Abstract]
Lastly, Herold et al (Sci Rep. 2017 Sep 25;7(1):12276) teaches and demonstrates that single and double mutations in exemplary antibodies, and found that single point mutations in the VH CDR region can completely abolish antigen binding. [see pg 8]
To provide adequate written description and evidence of possession of the claimed composition antibody genus, the instant specification can structurally describe representative antibodies or antigen binding fragments, that function to recognize SARS-CoV-2 spike protein receptor binding domain, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for antibodies that function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The SARS-CoV-2 spike protein RBD antigen provides no information about the structure of an antibody inhibits it.
In this instant case, the specification only discloses one example of an antibody that binds to SARS-CoV-2 spike protein RBD, and does not disclose any other representative variants having less than 100% SEQ ID NOS that function as claimed. The instant specification has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between functions (such as antigen specificity) and the structure of the antibody that specifically binds to SARS-CoV-2 spike protein RBD and the structure of the claimed antibody or antigen binding fragment thereof by a combination of such identifying characteristics, sufficient to show the Applicant was in possession of the genus of the antibody broadly encompassed by the claimed invention. Applicants have not established any reasonable structure-function correlation with regards to the sequences of the claimed antibody that can be altered and still maintain function. Therefore, one could not readily envision members of the broadly claimed genus.
Given the lack of representative examples to support the full scope of the claimed antibodies that bind to SARS-CoV-2 spike protein RBD, and lack of reasonable structure-function correlation with regards to the unknown sequences in the variable domains or CDRs of the antibodies that function as claimed, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibodies that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Claim 15 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 12, thereby treating the disease in said subject, wherein the disease comprises COVID-19, does not reasonably provide enablement for the method to prevent a disease, wherein the disease is COVID-19 or other corona-virus-related diseases, or a method to treat a disease, wherein the disease is coronavirus-related diseases or disorders.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
BREADTH OF THE CLAIMS: The claims are drawn to a method of preventing or treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 12, thereby preventing or treating the disease in said subject, wherein the disease comprises COVID-19 or other coronavirus-related diseases or disorders.
Thus, the claims are drawn to a method of preventing COVID-19 and all other coronavirus-related diseases or disorders, which is a vast list of disorders and diseases not only related to COVID-19 infection, but all coronavirus related diseases or disorders.
PRESENCE OR ABSENCE OF EXAMPLES: The instant specification does not recite any examples of the instantly claimed antibody that prevents COVID-19 or other coronavirus-related diseases or disorders, nor any examples of treating other coronavirus-related diseases or disorders.
STATE OF THE ART: A search of the prior art demonstrates that pharmacological treatment of COVID-19 includes vaccinations, hydroxychloroquine, azithromycin, and antivirals, and steroids. (see Bhimraj et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients With COVID-19 (September 2022). Clin Infect Dis. 2024 Jun 27;78(7):e250-e349). The art teaches that although vaccines are effective at reducing severe illness, preventing infection is not realistic.
For example, Table 19 presented herein is from the package insert of a SPIKEVAX injectable vaccine by ModernaTX, Inc. This vaccine has proven to be reliable at reducing the severity of COVID-19 infections. This version of the COVID-19 vaccine is a 2025- 2026 formula. Table 19 summarized the vaccine efficacy of SPIKEVAX at 93% in all 14, 287 participates tested. However, approximately 9.6 per 1,000 Persons of those receiving the vaccine still contracted COVID-19. Therefore, the SPIKEVAX vaccine has been proven to be effective, but it did not prevent infection in all recipients that received it.
The most successful compositions to prevent SARS-CoV-2 have been antibody cocktails instead of a single agent. Antibody cocktails are preferred because they significantly reduce the risk of the virus undergoing mutations and becoming resistant to the treatment as taught by Baum (Science. 2020 Aug 21;369(6506):1014-1018). Researchers often use combinations (cocktails) like Evusheld (tixagevimab and cilgavimab) or REGEN-COV (casirivimab and imdevimab). “Coronavirus-related diseases” are a broad group of diseases, Huang et al (Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol Sin. 2020 Sep;41(9):1141-1149) teaches that coronavirus disease 19 (COVID-1 or SARS-CoV-2) belongs to the β coronavirus family. Huang teaches the structure of SARS-CoV-2, which includes the spike (S) protein. Huang teaches that although there are sequence and structural similarities between SARS-CoV-2 and SARS-CoV S proteins, there is an opportunity to use agents that treat SARS-CoV-2 with agents with SARS-CoV, however, studies have shown that antibodies directed to SARS-RBD-directed monoclonal antibodies were unable to bind to SARS-CoV receptor binding domain (RBD). Huang further teaches that to prevent disease, combinations of different monoclonal antibodies that identify different epitopes would need to be assessed. Thus, the art demonstrates that: (1) COVID-19 and other coronaviruses are not completely prevented and (2) coronaviruses have various targets and one treatment for one coronavirus may not be applicable to another.
PREDICTABILITY: The specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent COVID-19 or all coronavirus related diseases, or treatment of all coronavirus related diseases. Reasonable guidance with respect to preventing any disease relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to particular types of coronaviruses. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of being exposed to the virus and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Reasonable correlation must exist between the scope of the claims and scope of enablement set forth, and it cannot be reasonably predicted that administration of the claimed antibody prevents COVID-19 or coronavirus or treats all coronaviruses-related diseases as claimed.
QUANTITY OF EXPERIMENTATION: Undue experimentation would be required to determine that the claimed antibody when administered to the population of subjects could predictably prevent coronaviruses and prevent or treat all coronavirus related diseases, as claimed. MPEP 2164.01 recites that “The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976)”. The experimentation needed to practice this method is undue and unreasonable as it requires determining whether the claimed antibody treats/prevents all coronavirus related diseases or prevents COVID-19. A person skilled in the art will not be able to use the invention without undue experimentation. (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988))
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 1-7 and 9-22 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 1 recites an isolated antibody or antigen binding fragment that specifically binds to SARS-CoV-2 spike protein. Claim 1 recites the CDR sequences of this antibody, and recites “SEQ ID NO: 10”. SEQ ID NO: 10 is less than 4 amino acids “FND” and sequences less than 4 amino acids are prohibited to be named “SEQ ID NO: XX” under ST.26. Thus, the claims are indefinite.
Claim 18 recites “A method of producing the recombinant polypeptide of claim 7, comprising introducing a polynucleotide encoding the recombinant polypeptide into a host cell and expressing the recombinant polypeptide in the host cell under a condition”. It is unclear what the conditions are in this claim and the instant specification does not define “under a condition.” Thus, the metes and bounds of the claims cannot be determined.
Examiner’s suggestion: Amend claim 18 and remove “under a condition”.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 5 recites “The antibody or antigen-binding fragment thereof of claim 1, wherein said antibody is a human antibody, a humanized antibody or a chimeric antibody.” The instant specification discloses that the antibody of claim 1, MR92250 is a monkey-human monoclonal antibody. Thus, the antibody was derived in animals and is outside the scope of claim 1 as the antibody cannot be fully human antibodies. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Closest Prior Art
The closet prior art made of record is Huang et al (Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol Sin. 2020 Sep;41(9):1141-1149). Huang et al teaches an antibody that binds to SARS-CoV-2 spike protein [pg 1145 2nd column-pg 1146, 1st column], however, does not teach that the antibody encompasses the instantly claimed sequences.
Conclusion
Conclusion: Claims 1-7 and 9-22 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 PM.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
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