Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Election/Restrictions
2. Applicant’s election without traverse of Group I, claims 1-11, in the reply filed on 01 December 2025 is acknowledged. Claims 1-11 are under consideration and claims 12-20 have been withdrawn.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 18 September 2023 and 29 September 2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
4. 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.
Claim Interpretation
5. In accordance with the Instant Specification, “a” and “an” include the plural unless the context clearly indicates otherwise (¶ [0035]) and “antibody” includes monoclonal, polyclonal, multi-specific, and antibody fragments (¶ [0037]). In addition, “containing” in claim 1 is interpreted to be open-ended language in accordance with MPEP 2111.03(I) and “a” is an indefinite article, and thus claim 1 reads on the full length or fragment thereof, and may include additional nucleotides/amino acids. “Comprising a sequence” in claims 2-3, 5-6, and 10-11 is interpretated in the same manner.
Claim Rejections - 35 USC § 112
6. 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.
7. Claims 1-11 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, “the antibody or antigen-binding fragment thereof comprising” can be interpreted to mean all the CDRs are on one molecule or they be on separate molecules since, as stated above, antibody includes polyclonal antibodies and these have more than one antibody species contained therein. Therefore, the claim has multiple structural interpretations.
Claims 2-11, which are dependent on claim 1, are similarly rejected.
Examiner suggests to add the word “monoclonal” before “antibody” to all of the claims.
Regarding claims 1-3, 5-6, and 10-11, “containing a sequence of” and “comprises a sequence of” an amino acid sequence can be interpreted as requiring the full sequence of the sequence recited or a partial sequence thereof. Therefore, these claims can have multiple structural interpretations.
Claims 2-11, which are dependent on claim 1, are similarly rejected.
See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.").
8. 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.
In making a determination as to whether an application has met the requirements forenablement under 35 U.S.C. 112 ¶ 1, the courts have put forth a series of factors. See, In reWands, 8 USPQ2d 1400, at 1404 (CAFC 1988). The factors considered include: (1) the breadth of the claims, (2) the nature of the invention, (3) the relative skill of those in the art, (4) the state of the prior art, (5) the level of predictability in the art, (6) the amount of direction or guidance provided, (7) the presence of absence of working examples, and (8) the quantity of experimentation necessary.
9. Claims 1-11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a monoclonal antibody comprising a full set of parental CDRs, does not reasonably provide enablement for any antibody molecule with fewer than all parental CDRs or mutated/truncated CDRs. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The breadth of the claims is found in claim 1 which recites an antibody or antigen-binding fragment thereof for binding PRRSV comprising a VH with SEQ ID NOs: 1-3 as CDRH1-3, respectively, and VL comprising SEQ ID NO: 4, KAS, and SEQ ID NO: 5 as CDRL1-3, respectively.
The nature of the invention is an antiviral antibody, as well as products and methods for making the same.
The level of skill of one of ordinary skill in this art is high.
The specification provides working examples for producing and sequencing an antibody with a full set of parental CDRs from mice, but does not provide working examples for any antibody molecule with fewer than all parental CDRs or mutated/truncated CDRs. In addition, most antibodies within the full breadth of the claims are highly unpredictable in function and would require an undue amount of experimentation in order to reproduce and use as discussed infra.
The instant claims read on a monoclonal or polyclonal antibody that have the full length or a fragment of the CDR sequences claimed. The fragments would amount to truncated/mutated CDRs which are not enabled to make a functional anti-PRRSV antibody. The polyclonal embodiment can have three or six CDRs per molecule and so each antibody molecule need not be defined by a full set (six) parental CDRs. Antibodies defined by fewer than all parental CDRs, in this case six, are not enabled. Similarly, claim 1 in line 3 makes clear that either the antibody or the antigen binding fragment comprising the VH and VL. Thus, the fragment need not comprise both at all. ¶ [0038] states the fragment can include an antigen binding site of the intact antibody and this reads on a single variable region or CDR. An antibody claimed by a single CDR is not enabled since this is not enough parental structure to find five other complementary CDRs. The minimal enabled antibody structure of a claim includes six complete parental CDRs.
10. The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”) (See PTO-892: Notice of References Cited). 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, which is characteristic of the 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 (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
Additionally, Bendig (Methods: A Companion to Methods in Enzymology, 1995, 8: 83-93) (See PTO-892: Notice of References Cited) reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3). It is noted that Bendig used Kabat CDRs in their humanization process (Pg. 86, Column 2, Paragraph, second). Similarly, the skilled artisan recognized a “chimeric” antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figures 1-3).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody comprising less than all six parental CDRs would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of a murine or humanized antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the antibody fragments and mutated antibodies of the instant claims as broadly as claimed.
In the case of antibodies, it is especially important to disclose which residues are permissive to mutation. 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 (Proc. Natl. Acad. Sci. USA, 1982, 79: 1979-1983) (See PTO-892: Notice of References Cited). Rudikoff 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 (Abstract).
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect antibody structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976). Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ 2d 1027 (CAFC 1991).
11. Furthermore, even if all claims recited monoclonal antibodies and both the antibody and antigen binding fragment required all currently recited CDRs, they would not be enabled since it is not clear that the CDR set is based on a CDR labeling system that yields CDRs that can be used, for example in humanization, to make a functional antibody with a new framework. Johnson (Methods in Molecular Biology, Antibody Engineering: Methods and Protocols, 2004, 248: 11-25) (See PTO-892: Notice of References Cited) teach that complete CDRs of antibodies CDRH1-3 and CDRL1-3 are at least 5, 16, 8, 11, 7, and 9 amino acid residues in length respectively (Pg. 12, Paragraph, second full). In instant claim 1, CDR-H2 has 8 residues, CDR-H3 has 13 residues, CDR-L1 has 6 residues, and CDR-L2 has 3 residues. These are significantly smaller than the CDR lengths of Kabat CDRs and so would not be expected to confer antigen binding to an antibody framework barring evidence to the contrary. They amount to no more than mutated Kabat CDRs.
Therefore, even a monoclonal antibody comprising the CDRs of claim 1 is not enabled. Barring experimental evidence, such mutated and truncated CDRs would be insufficient to confer antigen binding function. Applicant is requested to explain how they arrived at the instant CDR set. It is noted that Kabat CDRs and IMGT CDRs have been used in US patents to define antibodies. It is not clear that either of these systems applies to the instant CDRs, however.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by applicant, and the absence of working examples, undue experimentation would be required to make and use functional antibody molecules comprising fewer than all six complete parental CDRs with a reasonable expectation of success, absent a specific and detailed description in applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
12. Claims 7-11 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 isolated vectors and cells, does not reasonably provide enablement for unisolated vectors and cells. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The instant claims recite a vector or host cell, which includes transgenes and transgenic animals respectively since neither is isolated.
The nature of the invention products and methods for making an anti-viral antibody.
The level of skill of one of ordinary skill in this art is high.
The specification does not define “isolated”, “vector”, or “host cell” and thus these words will be given their broadest reasonable interpretation to one of ordinary skill in the art as discussed above. With respect to transgenes within animals and transgenic animals themselves, none were made here.
With respect to the unisolated host cells and vectors as transgenes, the state of the art at the time of filing was such that one of skill could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene (Wall et Al., Theriogenology, 1996, 45: 57-68) (See PTO-892: Notice of References Cited).
The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et Al., J. Biotechnol., 1994, 34: 269- 287) (See PTO-892: Notice of References Cited). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et Al., Current Opinions in Biotechnology, 1992, 3: 548-553) (See PTO-892: Notice of References Cited). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, 2009, 32: 107-121) (See PTO-892: Notice of References Cited) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second). Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce the antibody and antibody fragments of the instant claims.
The Examiner notes here, in addition to these issues, even assuming arguendo PHOSITA could make a host organism with functional transgene that encodes the instantly recited anti-PRRSV antibody, there is no predictability that the host will survive its expression. The transgene depends on the host for function and harm to the host, including death, renders the transgene nonfunctional and thus not enabled.
The art is well-aware of side effects caused by therapeutic antibodies such as the one instantly recited. In a transgenic cell or animal that expresses the same, the antibody will exert any possible side effect it can. It is not administered but chronically present and so such side effects are chronic and potentially more serious than any from an administered antibody. Hansel (Nat. Rev. Drug. Discov., 2010, 9: 325-337) (See PTO-892: Notice of References Cited) teaches in their table 1 on page 328 numerous exemplary side effects from licensed monoclonal antibodies to include: increased bleeding risk, infection, heart failure, cancer, thyroid disorder, autoimmune reactions, and cytokine release syndrome (CRS) to name only a few. One or more such effects, or similar, may occur with the therapeutic antibody instantly recited when administered and indeed be exacerbated by chronic exposure due to internal expression. The instantly encoded antibody may very well target related or unrelated proteins in the transgenic host, leading to such side effects. For all these reasons, transgenes in transgenic animals and the animals themselves are not enabled.
At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, is not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to recite the term "isolated" before the recitation, "host cell" and by amending the vector and polynucleotide claims to specify they are not in a transgenic animal using, for example “isolated”. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional transgenes and transgenic animals encompassed by the instant claims.
Art-Free Subject Matter
13. A monoclonal antibody comprising all six CDRs of claim 1 is currently free of the prior art.
Conclusion
14. No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA E LY whose telephone number is (571)272-5169. The examiner can normally be reached Monday - Thursday, 8:00 am - 5:00 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at (571) 270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KRISTINA E. LY/Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671