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
Acknowledgement is hereby made of receipt and entry of the communication filed on June 28, 2023. Claims 1, 4-5, 7-11, 13, 15, 17-18, 21 and 24-28 are pending and are currently examined.
Claim Objection
Claim 13 is objected to because of the following informalities:
There are two SEQ ID NO: 171 listed for LGSNRAS and MOALOTPFT. Based on the SLIC sequence disclosure, The MOALOTPFT (SEO ID NO:171) should be SEQ ID NO: 172.
There is no SEQ ID NO cited for TGSSSDVGGYDFVS. Based on the SLIC sequence disclosure, the CDR-L1 of TGSSSDVGGYDFVS should be SEQ ID NO: 196.
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 4, 13 and 15 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding clam 4 and 15, they require a heavy chain variable region comprising an amino acid sequence having at least 70% identity with the sequence of SEQ ID NO: 35 and SEQ ID NO: 1 respectively, and a light chain variable region comprising an amino acid sequence having at least 70% identity with the sequence of SEQ ID NO: 36 and SEO ID NO: 2 respectively.
Regarding claim 13, one of the second antibody or antigen binding fragment selections requires that (a) a light chain CDRl (CDR-Ll) comprising an amino acid sequence having at least 70% identity with the sequence RASOSVSSSYLA (SEO ID NO:80); a light chain CDR2 (CDR-L2) comprising the sequence GASSRAT (SEO ID NO:81); a light chain CDR3 (CDR-L3) comprising the sequence OOYGTSPWT (SEO ID NO:82); a heavy chain CDRl (CDR-Hl) comprising the sequence GFTFTSS (SEO ID NO:77); a heavy chain CDR2 (CDR-H2) comprising the sequence VVGSGN (SEO ID NO:78); and a heavy chain CDR3 (CDR-H3) comprising the sequence PSCSGGRCYDGFDI (SEO ID NO:79);
The written description rejection is made because the claims are interpreted as being drawn to an antibody or antigen binding fragment recited as being “at least 70% identity” to the instant claimed SEQ ID NOs: 1-2, SEQ ID NOs: 35-36, SEQ ID NOS; 80-82 and SEQ ID NOs: 77-79. This means that up to 30% amino acids sequences of the variable regions and CDRs can vary. The applicable standard for the written description requirement can be found in MPEP 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. v. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004).
The instant specification discloses an invention for neutralizing antibodies or antigen-binding fragments thereof against beta coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (See Abstract), and also discloses that a CDR region comprising or consisting of an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95% or 100% identity with certain sequences (See e.g. [0152] to [0158}, a FRI comprising or consisting of an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or 100% identity with the sequences of one of the light chain FRI (See e.g., [0195]) and an antibody or antigen binding fragment thereof comprises a heavy chain comprising a sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with one of the listed amino acid (See e.g., [0203]). However, the specification does not provide information disclosing what these variations are and does not disclose which portions of the claimed SEQ ID NOs: 1-2, SEQ ID NOs: 35-36, SEQ ID NOS; 80-82 and SEQ ID NOs: 77-79 are essential to retain the ability to be a functional antibody or which portions of SEQ ID NOs can be modified or altered up to 30% and still retain being a function antibody or antigen binding fragment.
The art relating to antibodies recognizes that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity that is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc. Natl. Acad. Sci. U.S.A., 1982, 79:1979-1983). Rudikoff et al. teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. The teachings in the art therefore indicate that the presence of both the first and second variable regions, with the indicated CDRs of those regions in the proper conformation, is required for the antigen binding proteins to bind the target antigens.
As for the framework regions (FR) of antibody disclosed in the instant specification, they are also critical for maintaining the overall structural integrity of the antibody. As an evidence, Wiens et al. (J Immunol. 1997 Aug 1;159(3):1293-302) teaches that mutations in FRW2 caused defective secretion at more than twice the frequency observed for mutations in CDR2 (See page 1297, right column, paragraph 2). Zhou et al. (Front Immunol. 2020 Jul 17; 11:1529) teaches that the FWRs help stabilize the antigen binding site and define the conformations of the CDR loops (See page 2, left column, paragraph 2) and few mutations can have a large impact on antigen binding (See page 2, right column, paragraph 1).
Accordingly, the specification does not provide written description to support that the applicant is in possession of the antibodies in a generic form in claims 4, 13 and 15. Thus, the claims 4, 13 and 15 are therefore rejected as lacking adequate descriptive support for the genus of antibodies with the CDRs or variable regions as required and not providing guidance on how such sequence changes should be made to up to 30% varies and still retain the antibody ability as claimed.
Claim Rejections - 35 USC § 112 (Enablement)
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 21, 24-28 contain subject matter which was not described in the specification in such a way as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. Enablement is considered in view of the Wands factors (MPEP 2164.01(a)) (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
These claims are directed to a method for preventing or treating a betacoronavirus infection or a related disease, or for reducing the risk of developing a betacoronavirus-related disease or the severity of a betacoronavirus-related disease, in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition as claimed.
The instant specification discloses a method for characterization of the antibody responses to SARS-CoV-2 Infection by the serological analysis (ELISA) and neutralization assays using the three SARS-CoV-2 seropositive serum samples and a HIV-based pseudoviral particles system expressing the full-length S protein of SARS-CoV-2 respectively (See instant specification, Example 1- [0262] to [0266]).
In the Examples 2-3 of the instant specification, the applicant discloses that the S2P- and RED-specific B cells from the PBMCs of patients (once serum neutralizing activities were confirmed) are isolated (See [0267]) and the mAbs, Mab #1-Mab #9, Mab #11-Mab #13, Mab #17, Mab #20-Mab #23, Mab #25, Mab #27, Mab #35-Mab #39, and Mab #41-Mab #48) are tested for the binding of the antigens (See [0268]-[0269]). Applicant specifically focuses on Mab # 25’s characterization in Example 3 for neutralizing additional SARS-CoV-2 variants of concern (VOCs) Alpha (B.1.1.7), Delta (B .1. 61 7 .2) and Gamma (P.1) and a more distantly related SARS-like bat coronavirus (See [0271]). Based on the Fig. 7F of the instant specification, the heavy chain of Mab# 25 is SEQ ID NO: 35 and the light chain of Mab# is SEQ ID NO: 36 with CDR regions at SEQ ID NOs: 207 and 209-213 as claimed in the base claim 1.
Base on the description above, the instant specification discloses the antibody, Mab#25, can neutralize all variants and WIV1 with comparable potency (FIG. 8A) (See [0271]) in vitro. However, the instant specification does not provide experimental evidences to support a method for preventing or treating a betacoronavirus infection or a related disease, or for reducing the risk of developing a betacoronavirus-related disease or the severity of a betacoronavirus-related disease in a subject in need as claimed. Based on the instant claim 21, the “preventing” and “treating” requires a method comprising administering to the subject an effective amount of a composition including the claimed antibody. However, the instant specification does not provide evidences for administrating an effective amount composition including the claimed antibody into a subject for supporting the “prevention” or “treating” effects, especially the “preventing” is general needed an animal challenge experiment for evaluations.
In addition, the instant specification also discloses that “Mab #25 was shown to bind equally well to peptides derived from SARS-CoV-1/2/WIV1, MERS-CoV, and HCoV-OC43, and to a slightly weaker extent to a peptide derived from HCoV-HKUl (FIG. 8H). However, despite binding to the stem helix peptide from MERS-CoV, HCoV-OC43 and HCoV-HKUl, Mab #25 did not recognize cell-surface expressed spikes from MERS-Co V, HCo V-OC43 and HCoV-HKU, and failed to neutralize a MERS-CoV pseudovirus or authentic HCoV-OC43, suggesting that the epitope is present but not equally accessible in the native conformation of the spike protein among the various coronaviruses. These results indicate that Mab #25 binds to a linear epitope on S2 that is conserved among beta coronaviruses and is able to neutralize sarbecoviruses (SARS-Co V- 1, SARS-CoV-2, WIV1) and the binding is unaffected by mutations found in several SARS-CoV-2 variants (See [0272]). Based on this description, the Mab#25 antibody can only recognize and binds to a linear (or sequential) epitope, and failed to neutralize any betacoronavirus as claimed in the in vitro neutralization experiments. At the same time, the instant specification does not provide supports to demonstrate the linear epitope-based antibody can prevent or treat a betacoronavirus infection or a related disease, or for reducing the risk of developing a betacoronavirus-related disease or the severity of a betacoronavirus-related disease in vivo through administrating an effective amount of composition as claimed. Furthermore, these is no “effective amount” of the pharmaceutical composition is disclosed in the instant specification.
Accordingly, when all the aforementioned factors are considered in total, it would require undue experimentation for one skilled in the art to practice the full scope of claimed invention as defined by instant claims 21 and 24-28. Therefore, claims 21 and 24-28 are rejected under 35 USC § 112 (Enablement).
Allowable Subject Matter
The amino acid sequences SEQ ID NOs: 209-211 and SEQ ID NOs: 207, 212 and 213 are free of prior art. Therefore, no prior art reference has been identified teaching or suggesting an antibody or an antigen binding fragment as claimed in claims 1, 7-11 and 17-18.
Accordingly, claims 1,7-11 and 17-18 would be allowable.
Conclusion
Claims 1, 7-11 and 17-18 are allowed. Claims 4-5, 13, 15, 21 and 24-28 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am to 4:30 pm, EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J. Visone can be reached on (571) 270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/RUIXUE WANG/ Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672