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 .
Claims 47-66 are currently pending and under consideration.
Drawings
The disclosure is objected to because of the following informalities: The drawings filed 03/28/2024 are objected for recitation of amino acid sequences (See Figure 4C) in the absence of a sequence identifier. See 37 CFR 1.821(c). 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825.
Claim Objections
Claim 46 is objected to because of the following informalities:
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The amino acid sequence of GFSLTSYGVH is associated with SEQ ID NO:2 and thus the claims have been interpreted this way. Please amend the parenthesis to “SEQ ID NO:2”.
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 47-66 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 broadly drawn to two sets of antibodies. The first set comprises antibodies that specifically bind to a human astrovirus capsid spike protein whose architecture is defined by six 6 CDRs such as:
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The second set claims no structure and only provides a function- “competes for binding” to the antibodies comprised within the first set. Thus, the second set of antibodies represents a genus comprising any number of potential antibodies with the function of competing for known antibodies. This second set of antibodies “are yet to be discovered” and the person of ordinary skill in the art would not recognize that applicants were in possession of this second set. However, what applicants are in possession of are seven monoclonal antibodies and antigen binding fragments thereof as set forth in Table 3- the monoclonal antibody 2D9 with CDRs comprising SEQ IDs 2-4(VH) and 6-8(VL), monoclonal antibody 3B4 with CDRs comprising SEQ IDs 10-12 (VH) and 14-16 (VL), monoclonal antibody 3E8 with CDRs comprising SEQ IDs 18-20 (VH) and 22-24 (VL), monoclonal antibody 3H4 with CDRs comprising SEQ IDs 26-28 (VH) and 30-32 (VL), monoclonal antibody 4B6 with CDRs comprising SEQ IDs 2, 34-35 (VH) and 37-39 (VL), monoclonal antibody 2A2 with CDRs comprising SEQ IDs 41-43 (VH) and 45-47 (VL), and monoclonal antibody 7C8 with CDRs comprising SEQ IDs 59, 50-51 (VH) and 53-55 (VL). The written description in this case does not extend to those antibodies that have yet to be discovered such as very diverse genus of antibodies that compete for binding to applicants’ seven structurally defined antibodies. Sela-Culang et al. (Fron. Immuno., Vol. 4, Article 302, Oct. 2013) reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition [e.g., pg. 1, abstract; pg. 3, “The Role of CDRs and their Definition”]. A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized [e.g., pg. 1, “The Motivations for…”]. Further, while identification of paratopes is often done through identification of CDRs, not all the residues within the CDRs bind the Ag. In fact, an early analysis of the 3-D structures of Abs suggested that only 20–33% of the residues within the CDRs participate in Ag binding (page 4).
A description of a genus of may be achieved by means of a recitation of a representative number of species, defined by structure, falling within the scope of the genus. However, the disclosure of seven species of monoclonal antibodies does not adequately extrapolate to a subgenus of yet-to-be discovered antibodies that have similar binding specificity. The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, inventor was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991). An applicant shows that the inventor was in possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). The claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties). In the instant case the seven disclosed antibodies all have particular CDRs that specifically bind to a capsid spike protein, and one of skill in the art would recognize that the inventor was not in possession of other monoclonal antibodies to a second genus comprising competing antibodies in view of the species disclosed.
Further, claim 54 is drawn to a fusion protein comprising “a chain” of an antibody of claim 47 fused to a heterologous sequence of amino acids. Applicants are not in possession of a fusion protein to “any” chain of claim 47. For example, this could include fusion to only a variable light chain. At the time of filing, antibody functionality were known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that that mutation to CDRs is unpredictable and that each construct requires function testing. For example, Herold et al. (Nature Scientific Reports, 7:12276, 25 Sep 2017) analyzes how framework regions and CDRs mutually influence antibody stability and function. Herold et al. teach that, in general, the exchange of conserved residues in the VL/VH interface did not have uniform effects on domain stability (abstract). The authors further teach that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected because antigen binding is “affected by each CDR loop differently” and changes thereto “can in principle affect antigen binding affinity in an unpredictable way” [e.g., pg. 14, ¶ 2]. Further, Herold et al. teach that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, ¶ 3].
Thus, at the time of filing, the prior art demonstrates that the binding of the capsid spike protein is possible (via the claimed 6 CDRs) by only the seven antibodies disclosed. The prior art does not teach a known structure activity structure activity relationship for a second genus of competing antibodies or to predicting CDRs residues that bind to a capsid spike protein solely by fusion protein comprising just a variable light chain polypeptide.
Claim Rejections - 35 USC § 102
(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.
Claim(s) 47-49, 50-51, and 61 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Espinosa et al. (Jnl. Virol., Vol.93, Issue 2, posted online October 24, 2018).
Espinosa et al. teach isolation of monoclonal antibodies that specifically bind to a human astrovirus (HAstV) capsid spike protein. In particular, monoclonal antibodies 3H4, 3B4, 4B6, 2D9, and 3E8 are taught on page 6 (see below) which recognized serotypes 1, 2, and 8. Absent evidence to the contrary, these are the same antibodies as disclosed in applicant’s specification in Table 3 beginning on page 49 and would naturally comprise the same claimed CDRs of Claim 47 and the variable heavy and light chains as set forth in Claim 48. The specification further indicates that full length antibodies are humanized and fused to the constant region of human IgG1 antibodies. Regarding claim 61, the claims read on the antibodies per se, as “suitable for administration” is an intended use.
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Claim Rejections - 35 USC § 103
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) 62-66 are rejected under 35 U.S.C. 103 as being unpatentable over Espinosa et al. (Jnl. Virol., Vol.93, Issue 2, posted online October 24, 2018) in combination with the teachings of Dubois et al. (Applicant’s IDS, WO 2016/149103).
Espinosa et al. teaches as set forth above regarding the claimed antibodies. Espinosa further teach (page 1) that human astroviruses (HAstVs) are common etiological agents of acute gastroenteritis in children, the elderly, and immunocompromised patients. HAstVs are classified into 8 classical serotypes (HAstV-1 to -8) associated with acute gastroenteritis. Espinosa teaches (page 2, 4th para. & page 10) that their laboratory studies provides the basis for the development of subunit vaccines to induce neutralizing antibodies and tools to explore the possibility of developing antibody therapy for astrovirus disease.
Espinosa does not specifically teach a method of treating a subject having a human astrovirus infection with the claimed antibodies (Claim 62) or treating a specific serotype (Claims 63-64) or that the subject to be treated has gastroenteritis or encephalitis.
Dubois et al. is in the same field of work as Espinosa et al., immunotherapy of astroviral infections. Dupois et al. teach and claim pharmaceutical compositions for treating human astrovirus infection by administering monoclonal antibodies. For example, Dubois et al. claim:
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Dubois et al. further teach (page 9) that immunoglobulin therapy was associated with the recovery of an immune-compromised patient with severe and persistent HAstV infection and that a therapeutic HAstV vaccine would significantly benefit human health by providing a treatment option for immune-compromised patients during astrovirus infection and providing a preventative measure for high-risk immune-compromised individuals. Dubois et al. further teach (page 9-10) that the therapeutic monoclonal antibodies are “expected to be highly safe for immune- compromised individuals, and would have low side effects, low toxicity, and require infrequent dosing”.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to have treated a subject having a human astrovirus infection comprising administering any one of the anti-HAstV monoclonal antibodies of Espinosa et al. because Espinosa et al. taught that that human astroviruses (HAstVs) are common etiological agents of acute gastroenteritis in children, the elderly, and immunocompromised patients and that human astrovirus neutralization provides a basis for developing antibody therapy for astrovirus disease. Similar to the laboratory work of Espinosa et al., Dubois et al. teaches and claims monoclonal antibody therapy for the treatment of astrovirus infection including those subjects with gastroenteritis. The combination of the two references would provide the motivation to use the antibodies to treat an HAstV because the antibodies are designed to specifically neutralize the virus. Further, one would have been motivated to use the antibodies because Dubois et al. taught that immunoglobulin therapy was associated with the recovery of an immune-compromised patient with severe and persistent HAstV infection, and therapeutic HAstV vaccine would significantly benefit human health by providing a treatment option for immune-compromised patients during astrovirus infection and providing a preventative measure for high-risk immune-compromised individuals. Moreover, Dubois taught that therapeutic monoclonal antibodies are “expected to be highly safe for immune- compromised individuals, and would have low side effects, low toxicity, and require infrequent dosing”.
Claim(s) 52-60 are rejected under 35 U.S.C. 103 as being unpatentable over Espinosa et al. (Jnl. Virol., Vol.93, Issue 2, posted online October 24, 2018) in combination with the teachings of Crowe et al. (US20210324050, effectively filed 08-27-2018).
Espinosa et al. teach as set forth above regarding neutralizing anti-HAstV monoclonal antibodies.
Espinosa et al. do not specifically teach antigen-binding fragments (e.g., Fab, F(ab’)2, F(ab’) or single chain antibodies (Claim 52), bispecific antibodies (Claim 53), fusion proteins comprising chains of the antibodies (Claim 54), an agent conjugated to the antibodies (Claim 55), methods to recombinantly express the antibodies with vectors and host cells (Claims 56-60).
However, these are all well-known laboratory procedures and would have been prima facie obvious to one of ordinary skill in the art at the time of filing as evidence by the teachings of Crowe et al.
Crowe et al. teaches teaches [0007,0009, 0050] methods of detecting and treating a subject infected with norovirus comprising contacting a sample from a subject or delivering to the subject an antibody or antibody fragment. Crowe et al. teaches [0009,0136] that the antibody fragment may be a recombinant scFv (single chain fragment variable) antibody, Fab fragment, F(ab′)2 fragment, or Fv fragment. Crowe further teaches [0187] that the antibodies can be bispecific. For example, some bispecific antibodies may also be used to localize cytotoxic agents to infected cells. These antibodies possess a pathogen-binding arm and an arm that binds the cytotoxic agent (e.g., saporin, anti-interferon-α, vinca alkaloid, ricin A chain, methotrexate or radioactive isotope hapten) which encompasses an agent conjugated to the antibodies or a fusion protein comprising a binding domain of the antibody. The reference further teaches [0106] that the antibodies may be obtained by molecular cloning wherein nucleic acids such as RNA can be isolated and antibody genes amplified by RT-PCR and cloned into an immunoglobulin expression vector. Also, recombinant full-length IgG antibodies can be generated by subcloning heavy and light chain Fv DNAs from the cloning vector into an IgG plasmid vector, transfected into 293 (e.g., Freestyle) cells or CHO cells, and antibodies can be collected and purified from the 293 or CHO cell supernatant [0132]. Expression of nucleic acids encoding antibodies, both for the purpose of subsequent antibody purification, and for immunization of a host is also taught by the reference [0133]. Alternatively, DNA encoding the antibody may be employed for the same purposes. The DNA is included in an expression cassette comprising a promoter active in the host cell for which it is designed. The expression cassette is advantageously included in a replicable vector, such as a conventional plasmid or minivector [0134]. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) discloses that "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results". In the instant case, all of the claimed elements and laboratory procedures 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 to yield stable antibody formulations as claimed.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643
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