DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s election without traverse of Group II (drawn to a method of treating a condition or disease by administering an antibody) and the species of SEQ ID NO:234 in the Response filed on July 16, 2026 is acknowledged.
Claim 2 has been canceled.
Claims 1 and 3-21 are pending.
Claims 1 and 3-12 have been withdrawn under 37 CFR 1.142(b) as being drawn to nonelected invention.
Claims 13-21 are currently under consideration as they read on the elected invention.
3. 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.
4. Claims 13-21 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.
A) Claims 13-21 are indefinite in that they recite the number of amino acid positions without providing the numbering system. There are several numbering systems used when referring to the amino acid positions in the Fc region. For example, Presta (US 6,737,056) teaches that EU and Kabat are two different systems. In Table 6, Presta teaches that S239 in EU numbering is also referred as position 252 in Kabat. It is suggested that the claims be amended to recite the particular numbering system used (e.g. EU numbering system if there is support in the instant specification).
B) claim 14 is indefinite in the recitation of “wherein the antibody (a) does not contain a mutation at A330 and/or P331 that reduces effector function and/or (b) does not contain the mutation A330S or P331S” because the metes and bounds of the claim is unclear. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim encompasses the broad recitation “does not contain a mutation at A330 and/or P331”, and the claim also recites “and/or does not contain the mutation A330S and/or P331S” which is the narrower statement of the range/limitation. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is a merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
5. 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.
6. Claims 13-21 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.
The claims are drawn to a method of treating a condition or disease in a subject comprising administering an antibody comprising a heavy chain constant region comprising mutations L234A, L235E, and G237A, wherein the antibody has reduced effector function relative to the same antibody without these mutations, and wherein the antibody does not bind to TIM3 or TIGIT. Dependent claim 14 further recite that the antibody does not contain a mutation at A330 and/or P331 that reduced effector function and/or does not contain the mutation A330S or P331S. Dependent claim 17 further recite that the antibody binds to an inhibitory receptor on an immune cell. Dependent claim 21 further recite that the antibody is an antagonist of a checkpoint inhibitor or an agonist of a checkpoint stimulator.
The specification discloses working examples of IgG1 anti-TIM3 antibody consisting L234A, L235E, G237A, A330S, and P331S substitutions is devoid binding to CD16, CD32a, CD32b, and CD64 and removing A330S and P331S substitutions did not significantly affect the inertness of the Fc (e.g. see Example 14 in page 121 of the specification as-filed).
There is insufficient written description in the specification as-filed of the antibody comprising a heavy chain constant region comprising the mutations of L234A, L235E, and G237A, and the antibody does not bind to TIM3 or TIGIT for the method of treating an unspecified disease or condition as recited in the instant claims.
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 Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection). 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.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), the following is noted. To show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Further, an adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Indeed, the 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.
Artisans are well aware that knowledge of a given antigen (for instance human CD40) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) 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. (Protein Engineering Design & Selection 2009, 22;3:159-168) 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. (The Journal of Immunology, 2004, 173:7358-7367) 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). 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. (Nature Review Immunology, 2019, 19: 355-368) 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).
It is noted that applicant has not claimed a product, but rather a method of administering a product. However, artisans must reasonably be in possession of a product in order to be in possession of methods of administering said product. The only structure recited in the instant claims are the three mutations L234A, L235E, and G237A that would reduce the effector functions and the antibody does not bind TIM3 or TIGIT. However, the structure of an antibody comprising the recited three mutations and what antigen it does not bind are not sufficient to correlate to the function of treating an unspecified condition or disease in a subject.
Thus, all present claims utilize only functional language to describe the product which is necessarily administered in the instant claims. The specification discloses specific antibody, e.g. anti-TIM3 antibody.
The specification discloses laundry list of antibodies, such as anti-PD1 antibodies. Such disclosure does not serve to provide a written description of an antibody comprising a heavy chain constant region comprising L234A, L235E, and G237A mutations and wherein the antibody does not bind TIM or TIGIT as it does not identify any specific structural feature or combination of features which give rise to the functions, e.g. antigen binding, and thus could be used to treat any or all disease or condition.
Further, given the fact that the administered an antagonist of a checkpoint inhibitor or an agonist of a checkpoint stimulator can both be administered, there does not appear to be any reasonable shared structure present in the genus of recited antibody which gives rise to their functional activity.
It is noted that the specification does disclose in vitro working example of anti-TIM3 antibody consisting of L234A, L235E, and G237A mutations in the Fc region. However, this single antibody species is not reasonably representative of the species of all antibody for the method of treating a disease or condition, wherein the antibody does not bind TIM3 or TIGIT because of the structural diversity found in antibodies that bind the same antigen as discussed by for example Edwards et al., Llyod et al., and Goel et al. discussed above.
Further, identifying an antibody simply on the basis of what it does not bind rather than by identifying the sequence/structure of the antibody in question is insufficient to provide sufficient written description of the antibody in question.
Therefore, in view of the breadth of the claims and the generic nature of the instant specification, artisans would reasonably conclude that applicant was not in possession of the full breadth of the antibody at the time the instant application was filed. Logically, if applicant was not in possession of the agent which is being administered, applicant also was not in possession of methods of administering such reagents at the time the instant application was filed.
7. Claims 13-21 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.
The claims are drawn to a method of treating a condition or disease in a subject comprising administering an antibody comprising a heavy chain constant region comprising mutations L234A, L235E, and G237A, wherein the antibody has reduced effector function relative to the same antibody without these mutations, and wherein the antibody does not bind to TIM3 or TIGIT. Dependent claim 14 further recite that the antibody does not contain a mutation at A330 and/or P331 that reduced effector function and/or does not contain the mutation A330S or P331S. Dependent claim 17 further recite that the antibody binds to an inhibitory receptor on an immune cell. Dependent claim 21 further recite that the antibody is an antagonist of a checkpoint inhibitor or an agonist of a checkpoint stimulator.
The specification discloses working examples of IgG1 anti-TIM3 antibody consisting L234A, L235E, G237A, A330S, and P331S substitutions is devoid binding to CD16, CD32a, CD32b, and CD64 and removing A330S and P331S substitutions did not significantly affect the inertness of the Fc (e.g. see Example 14 in page 121 of the specification as-filed).
The specification does not enable any person skilled in the art to which it pertains, or with which it is most clearly connected, to make and use the invention commensurate in scope with these claims.
The instant specification has not provided sufficient biochemical information (amino acid composition) that distinctly identifies the antibody comprising a heavy chain constant region comprising mutations L234A, L235E, and G237A wherein the antibody does not bind TIM3 or TIGIT.
There is insufficient direction and guidance in the specification which enables the skilled artisan to make and use claimed method of treating any or all condition or disease by administered the antibody defined by three mutations in the Fc region and does not bind TIM3 or TIGIT, commensurate in scope with the claimed invention.
The instant specification has not enabled the breadth of the claimed invention in view of the teachings of the specification. Factors to be considered in determining scope and enablement are: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented in the specification, 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. See Ex parte Forman, 230 USPQ 546, BPAI, 1986.
The instant specification has not disclosed how to make and use the claimed antibody and methods to treat any or all condition or disease. There is insufficient evidence of the invention with respect to the in vitro experiment based on anti-TIM3 antibody can provide guidance and directions for a method of treating a condition or disease by administering an antibody that does not bind TIM3 or TIGIT.
Pharmaceutical therapies in the absence of in vivo clinical data are unpredictable for the following reasons; (1) the protein may be inactivated before producing an effect, i.e. such as proteolytic degradation, immunological inactivation or due to an inherently short half-life of the protein; (2) the protein may not reach the target area because, i.e. the protein may not be able to cross the mucosa or the protein may be adsorbed by fluids, cells and tissues where the protein has no effect; and (3) other functional properties, known or unknown, may make the protein unsuitable for in vivo therapeutic use, i.e. such as adverse side effects prohibitive to the use of such treatment. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO Bd. Pat App. & Inter. 1992).
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 Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection). 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 CD40) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) 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. (Protein Engineering Design & Selection 2009, 22;3:159-168) 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. (The Journal of Immunology, 2004, 173:7358-7367) 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). 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. (Nature Review Immunology, 2019, 19: 355-368) 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).
Here, the disclosure of specific antibodies, such as anti-TIM3 antibody consisting of L234A, L235E, and G237A mutations in the Fc region and in vitro experimental data disclosed in the specification is insufficient to enable the breath of methods of treating unspecified condition or disease by administering an antibody defined by the heavy chain constant region mutations and the antigens the antibody does not bind.
Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention. See Genentech, Inc. v. Novo Nordisk A/S 42 USPQ2d 1001, 1005 (Fed. Cir. 1997) quoting In re Wright, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
In view of the lack of predictability of the art regarding make and use of a genus of antibody, undue experimentation would be required to practice the claimed methods with a reasonable expectation of success, absent a specific and detailed description in applicant's specification of how to effectively practice the claimed methods and absent working examples providing evidence which is reasonably predictive for the claimed products and methods of treating a condition or disease.
8. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
9. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
10. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(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.
11. Claims 13-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al. (US 2015/0353637) as evidenced by the instant specification in [0213].
Wang et al. teach an anti-glucocorticoid-inducible TNF receptor (GITR) antibody and its use in therapeutic applications such as cancer treatment (e.g. see Abstract). Wang et al. further teach that GITR is constitutively expressed in regulatory T cells (e.g. see [0002]). Wang et al. teach that the Fc region of the antibody can be substituted in positions L234A, L235E, and G237A for reduced FcγR binding (eg. See [0595]). Wang et al. further teaches IgG1.1f consisting of L234A, L235E, and G237A (e.g. see [945] and SEQ ID NO:9 in Table 11).
These teachings of Wang et al. including SEQ ID NO:9 do not have A330S and P331S substitutions. Wang et al. teach that the anti-GITR antibody can be administered to treat variety of disease (e.g. see [0728]-[0729]).
The SEQ ID NO:9 disclosed in Wang et al. is 99.4% identical to the instant SEQ ID NO:234 and without C-terminal lysine, see sequence alignment below (Qy: instant SEQ ID NO:243, Db: prior art SEQ ID NO:9):
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As evidenced by the instant specification in [0213], anti-GITR antibody is a checkpoint stimulator agonist. Given that the prior art antibody comprises identical amino acid mutations L234A, L235E, and G237A in the Fc region as the instant antibody, the prior art antibody would inherently have the reduced effector functions including ADCC and CDC.
Therefore, the reference teachings anticipate the instant invention.
12. No claim is allowed.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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