DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s preliminary amendments received April 7, 2023 are acknowledged.
Claims 1-11, 18, and 19 have been amended,
Claims 1-19 are pending in the instant application.
Claims 1 and 11 are independent.
Applicant’s election without traverse of the invention of group II, drawn to anti-ITGIT antibodies, presently claims 11-16, in the reply filed on December 30, 2025 is acknowledged.
Claims 1-10 and 17-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 30, 2025.
Claims 11-16 are under examination in this office action.
Information Disclosure Statement
The IDS forms received 7/21/2023 and 1/7/2025 are acknowledged and the references cited therein have been considered.
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 11, 12, and 14-16 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.
Applicant has broadly claimed antibodies that bind T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT). The broadest claims do not actually recite any antigen specificity whatsoever and require the CDR3 sequences of the VH and VL domains to comprise specific sequences recited by SEQ ID number, with dependent claims reciting antigen specificity (claim 12) as well as defining all six CDRs by SEQ ID number (claim 13). Such antibodies are further recited as comprising Fc domains (claims 14-16). To support such breadth, the specification discloses the synthesis of the anti-TIGIT antibody M1-8 using standard murine hybridoma technology (see working example 1, and note that M1-8 has a VH/VL pair of SEQ ID NOs:7 and 8 respectively wherein SEQ ID NO:7 comprises SEQ ID NOs:2, 3, and 4, and SEQ ID NO:8 comprises SEQ ID NO:5, YAS, and SEQ ID NO:6). No working examples concerning production of antibody variants, such as via CDR mutagenesis, appear to be disclosed.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by 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 applicant was in possession of the genus. See MPEP 2163. In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.” The court has further stated that “Adequate written description 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.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014). Such cases have indicated that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not provide information as to what an antibody binding that antigen necessarily looks like (i.e. the primary amino acid structure of the antibody). Applicant is reminded that the courts have long ruled that “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of an antibody (such as its ability to bind TIGIT) does not provide evidence of possession of the antibody itself. Further, courts have long ruled that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005). Also, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, 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 which is characteristic of the parent immunoglobulin (Janeway et al., see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., and Winkler et al., see entire documents). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
Artisans are well aware that knowledge of a given antigen (for instance human TIGIT) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al. teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, as their sequencing studies revealed that out of 841 unselected and 5,044 selected antibodies, all but one of the 49 functional VH gene segments was observed (see entire document). Goel et al. disclose the synthesis of three mAbs that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen. Indeed, Kanyavuz et al. teach that “Theoretically, under physiological conditions, the human immune system can generate BCRs with 1026 distinct sequences, an astronomical number that is far greater than the calculated number of all B cell clones that can be generated during the lifespan of a healthy human (estimated to be 4 × 1014).
As discussed above, applicant discloses immunizing mice with human TIGIT and recovery of antibodies using standard hybridoma technology, most specifically the M1-8 antibody. In independent claim 11 applicant has claimed an antibody that comprises the CDR3 sequences of SEQ ID NOs:4 and 6 in the VH and VL respectively, yet no antigen specificity is recited. However, as evidenced by Janeway et al. even though the CDR3 sequences are important, all of the CDRs are needed for the function of antigen binding. It should be pointed out that if the sequences are not recited, reasonably random sequence can be used and based upon art teachings including Rudikoff and Winkler that even a single CDR change can abrogate binding, having four CDRs be random sequence reasonably will not support the function of antigen binding as all six CDRs are needed as per the Janeway textbook. The presence of an Fc domain reasonably does nothing with regard to the function of antigen binding, and as discussed at the beginning of the office action antibodies that bind an antigen cannot reasonably be claimed simply by identifying the antigen as the number of potential antibody sequences that have such a function literally can be astronomical. As far as the instant application disclosing a representative number of species to satisfy written description, the only species which appears to be disclosed is M1-8 itself and a single antibody is not reasonably representative of such breadth.
Therefore, in view of the breadth of the claims artisans would reasonably conclude that while applicant was in possession of the anti-TIGIT antibody M1-8 and antibodies that bind TIGIT and comprise all six CDRs of M1-8 (i.e. SEQ ID NOs:2-5, YAS, SEQ ID NO:6, which includes antibodies comprising the VH and VL domains of SEQ ID NOs:7 and 8 respectively), applicant was not in possession of the full breadth of antibodies recited by way of partial sequences. Amendment of the claims to minimally require that the anti-TIGIT antibodies comprise six fully defined CDRs known to collectively be capable of binding TIGIT when present as a set of six sequences, such as is presently recited in claim 13 (which is not a party to the instant rejection) is one possible approach to obviating the issues discussed above.
Claims 11, 12, and 14-16 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant has claimed a genus of antibodies that bind “T-cell immunoreceptor with immunoglobulin and ITIM domains” also known as TIGIT and zB7R1. Anti-TIGIT antibodies and their administration to treat disease are known in the prior art (see for example WO 2017/037707). The instant claimed antibodies are recited as having some amount of biological sequence information as recited by SEQ ID number, with the independent claim reciting only the CDR3 sequences for the variable heavy and variable light antigen binding domains, while all six CDRs are recited in dependent claim 13. The instant specification discloses the generation of the M1-8 anti-TIGIT antibody using standard hybridoma technology in working example 1, and no working examples concerning CDR mutagenesis or binding studies wherein less than a complete antigen binding domain comprising a cognate VHVL pair (and its embedded six CDRs) was demonstrated to have antigen binding activity. Thus, the instant claims are significantly broader in scope that the working examples as the claimed antibodies a) are not recited as actually binding the TIGIT antigen (apart from dependent claim 12) and b) even if amended to recited antigen binding specificity the independent claim only requires two CDRs defined by SEQ ID number, rather than the six CDRs found in conventional structure antibodies comprising a paired VH and VL.
It is well known in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, 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 which is characteristic of the parent immunoglobulin (Janeway et al., see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., and Winkler et al., see entire documents). In the instant independent claim, the claimed antibodies are required to comprise specific biological sequences recited by SEQ ID number, and thus the only reasonable way to make such reagents is using the tools of molecular biology and recombinant antibody production. However, concordant with the teachings of Janeway et al., such recombinant production typically requires six CDR sequences for conventional structure antibodies (Kipriyanov et al., see entire document). As has already been stated, the independent claim defines only 2 out of the 6 CDR sequences reasonably needed to make an antibody using the techniques of recombinant antibody production, and thus the biological sequences of the four undefined CDRs reasonably encompass totally random sequence. Given that CDR alterations as small as a single CDR can abrogate antigen binding activity as shown by Rudikoff et al. and Winkler et al., it does not appear reasonable that such a large amount of random sequence will maintain antigen binding activity, and no working examples demonstrating that the presence of only the CDR3 sequences of the M1-8 clone confer antigen binding activity have been provided. Therefore artisans cannot reasonably make the antibodies as presently claimed in the absence of extensive unpredictable basic science research and experimentation. Recitation of antigen specificity and six fully defined CDR sequences is strongly recommended.
Claim Objections
Claims 11-13 are objected to for informalities.
Specifically, claim 12 recites “TIGIT” which is really an abbreviation that stands for “T-cell immunoreceptor with immunoglobulin and ITIM domains” as set forth on page 1 of the instant specification. Thus, TIGIT should be spelled out in full at its first appearance in the claim set, accompanied by the abbreviation in parenthetical notation, with dependent claims reciting the abbreviation. It is noted that claim 12 is a dependent claim and as such it is very strongly recommended that the antigen specificity for the antibody be added to the independent claim.
Claim 13 is objected to as being dependent upon a rejected independent claim, but would be allowable if rewritten in independent form including all of the limitations of the independent claim and any intervening claims which in the present case also includes antigen specificity.
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Michael Szperka whose telephone number is (571)272-2934. The examiner can normally be reached Monday-Friday 8:30-5:00.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641