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 amendment, filed on 08/15/2023, is acknowledged.
3. Claims 1-18 are pending.
4. Applicant’s IDS, filed 08/15/2023 and 10/31/2024, is acknowledged.
5. Claims 5-6, 8-9 are objected to because the claim recites “the cells” and “to cells” in plural form, however base claim 1 recite “a cell” in the singular form. Consistency is required.
6. Applicant states that this application is continuation (CON) application of the prior-filed application. A continuation application cannot include new matter. Applicant is required to change the relationship (continuation or divisional application) to continuation-in-part because this application contains the following matter not disclosed in the prior-filed application: Instant claim 1 recites a new” method of delivering an isolated monoclonal antibody or an antibody fragment thereof to a cell comprising contact the cell with the isolated monoclonal antibody . . .”. However, the prior-filed application does not contemplate methods of “delivering” the claimed antibodies to “any cell” for no purpose. The prior-filed application examples are directed to contacting specific cells. Example 10. Used tumor cells A549, U373, HCT116, HCT116 and Mel-624 was examined using MTT cell survival assay in the presence of anti-PVR mAb. Example 9 of the specification test the effect of the anti-PVR mAbs on T cell proliferation using PBMC cell. Example 8 uses RPMI-8866 cel line, or B16 cells. Examples 6 and 7 uses HepG2 hepatocellular cancer cells,
The specification does not contemplate a broad genus of methods of delivering the claimed antibodies to a broad genus of cells. The specification fails to contemplate the instantly claimed genus of cells. Applicant is creating a genus of cells that were not contemplated in the specification as originally or claims filed. A subgenus is not necessarily implicitly described by a genus encompassing it and a species upon which it reads, see In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972). Obviousness is not the standard for the addition of new limitations to the disclosure as filed. It is noted that entitlement to a filing date does not extend to subject matter which is not disclosed, but would be obvious over what is expressly disclosed. Lockwood v. American Airlines Inc., 41 USPQ2d 1961 (Fed. Cir. 1977).
Claims 1-3 were presented only in the instant application, filed 08/15/2023, and the specification and claims as originally filed do not provide a clear support of "delivering an isolated monoclonal antibody or an antibody fragment thereof to a cell". “A cell” is not equivalent to tumor cells, MTT cells, T cell proliferation, or RPMI-8866 cell. The instant claims now recite limitations which were not clearly disclosed in the specification and recited in the claims as originally filed. Accordingly, the priority is set at the filing data of the instant application 08/15/2023 for claims 1-3. The priority for claims 4-18 is set at the filing date of the provisional application 62/301,727 which is 03/01/2016.
7. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
8. Claim 1-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10906987 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because claims of the '987 patent anticipate claims 16-17 and render obvious at least claims 1-15 and 18 in the instant application (see analysis below).
Claims 16-17 are anticipated by claims 1-11 of the `987 patent because the `987 patent claims anti-PVR antibody comprising the CDRs of antibodies 4E5, 5B9 and 7D4 recited instant claim 116-17.
Alignment between claimed SEQ ID NOs: 36-38-40 and patented SEQ ID NO: 34 and 77.
Qy 1 GYTFSNYWIE--------------EIFPGSGRINFNEKFKG------------------- 27
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Db 24 GYTFSNYWIEWIKQRPGHGLEWIGEIFPGSGRINFNEKFKGKATFTADTSSDTTYMQLSS 83
Qy 28 -------------TKIYGNSFDY 37
||||||||||
Db 84 LTSADSAVYYCARTKIYGNSFDY 106
Alignment between claimed SEQ ID NOs: 85-59-48 and patented SEQ ID NO: 42 and 79.
Qy 1 KASQDVGTAV----------------WASSRHE--------------------------- 17
|||||||||| ||||||
Db 24 KASQDVGTAVVWYQQKPGQSPKLLIYWASSRHNGVPDRFTGSGSGTDFTLTISNVQSEDL 83
Qy 18 -----QQYSRYPLT 26
|||||||||
Db 84 SDYFCQQYSRYPLT 97
Regarding 1-15 and 18, instant application and the '987 patent share at least one inventor and/or assignee (e.g., Yissum Research Development Company of the Hebrew Univ). Further, the '987 patent is related to the instant application as a CON and thus no "121 shield" exists here. See filing receipt. See also MPEP § 804.01. See also Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d 1353, 1362 (Fed. Cir. 2008) (“the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications … This is true even if the … application was mistakenly filed … and should have been filed as a DIV application.”). See also Amgen Inc. v. F. Hoffmann-La Roche Ltd., 580 F. 3d 1340, 1354 (CAFC 2009) (“Amgen does not dispute that it denominated the '178 and '179 applications continuations, that it checked the continuation application box on the submitted form, or that its applications met the PTO's definition of a continuation application in MPEP § 201.07. … Instead, Amgen argues that, because the '178 and '179 continuation applications could have been filed as divisional applications, we should treat them as such for purposes of § 121. While this argument convinced the district court to regard the '178 and '179 continuation applications as divisional applications, we are not likewise convinced. We decline to construe ‘divisional application’ in § 121 to encompass Amgen's properly filed, properly designated continuation applications.”).
Accordingly, it would have been prima facie obvious to use the antibodies set forth in claims 1-15 and 18 for “delivering an isolated monoclonal antibody or an antibody fragment thereof to cell comprising contacting the cell with the isolated monoclonal antibody or antibody fragment thereof ” before the effective filing date. See Sun Pharmaceutical industries v. Eli Lilly and Co., 611F. 3d 1381, 1385 (CAFC 2010) (“our prior obviousness-type double patenting decisions in Geneva and Pfizer . … we found claims of a later patent invalid for obviousness-type double patenting a method of using the compound for a use described in the specification of the earlier patent”). See also MPEP § 804(II)(B)(2)(“in AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (fed. Cir . 2014), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context.”)
The § 121 safe harbor, “by its literal terms, protects only divisional applications (or the original application) and patents issued on such applications.” Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 1360 (Fed. Cir. 2008) (internal quotation marks omitted).
9. Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 56-74 of copending Application No. 17764373 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the `373 application directed to humanized anti-PVR antibody, NB0941 comprising the claimed CDRs of antibody 5B9 having the CDRs (WASSRHNG).
Aligment of claimed CDRs of SEQ ID NO: 85-59-48 with referenced SEQ ID NO: 2,7.
Qy 1 KASQDVGTAV----------------WASSRHE--------------------------- 17
|||||||||| |||||||
Db 24 KASQDVGTAVVWYQQKPGKAPKLLIYWASSRHEGVPDRFSGSGSGTDFTLTISSLQPEDF 83
Qy 18 -----QQYSRYPLT 26
|||||||||
Db 84 ADYFCQQYSRYPLT 97
Alignment of claimed CDRs of SEQ ID NO: 36-38-40 with referenced SEQ ID NO:1 3, 5, 6.
Qy 1 GYTFSNYWIE--------------EIFPGSGRINFNEKFKG------------------- 27
|||||||||| |||||||||||||||||
Db 26 GYTFSNYWIEWVRQAPGQGLEWMGEIFPGSGRINFNEKFKGRVTFTADTSISTAYMELSR 85
Qy 28 -------------TKIYGNSFDY 37
||||||||||
Db 86 LRSDDTAVYYCARTKIYGNSFDY 108
The `373 applicant claims that methods of increasing surface expression and/or signaling of CD226 in the CD8+ T or NK cells of an individual comprising administering to the individual a therapeutically effective amount of the humanized antibody or antigen binding fragment thereof. Methods of treating a cancer in an individual afflicted with a cancer comprising administering to the individual a therapeutically effective amount of the humanized antibody or antigen binding fragment thereof. Method of treating a cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the scFv. The instant claims are anticipated by the `373 application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
10. Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 40-59 of copending Application No. 18993887 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the `887 application directed to ADC comprising humanized antibody anti-PVR antibody comprising VH-CDR1-3 of claimed SEQ ID NOs: 84-38-40 and VL-CDR1-3 of SEQ ID NO: 44-59-48.
Alignment of claimed SEQ ID No: 84-38-40 with referenced SEQ ID NOs: 1.
Qy 1 SNYWIE--------------EIFPGSGRINFNEKFKG----------------------- 23
|||||| |||||||||||||||||
Db 30 SNYWIEWIKQAPGQGLEWIGEIFPGSGRINFNEKFKGRVTFTADTSISTTYMELSRLRSD 89
Qy 24 ---------TKIYGNSFDY 33
||||||||||
Db 90 DTAVYYCARTKIYGNSFDY 108
Alignment of claimed SEQ ID No: 44-59-48with referenced SEQ ID NOs: 2.
Qy 1 KASQDVGTAVV---------------WASSRHE--------------------------- 18
||||||||||| |||||||
Db 24 KASQDVGTAVVWYQQKPGKAPKLLIYWASSRHEGVPDRFTGSGSGTDFTLTISSLQSEDF 83
Qy 19 -----QQYSRYPLT 27
|||||||||
Db 84 ADYFCQQYSRYPLT 97
The `887 further teaches methods of treating a cancer in an individual in need of such treatment, the method comprising administering to the individual a therapeutically effective amount of the pharmaceutical composition comprising the claimed ADC, wherein the cancer is selected from the group consisting of prostate cancer, ovarian cancer, colorectal cancer, breast cancer, pancreatic cancer, liver cancer, lung cancer, glioblastoma, adrenal cancer, uterine cancer, testis cancer, and head and neck cancer. The claims of the `887 publication anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
11. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(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.
12. Claims 1-18 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.
Claims 1 and dependent claims thereof encompass the use of a abroad genus of antibodies comprising mixing 6 CDRs derived Kabat and IMAG system of antibodies 4E5 or 5B9 or 7D4 without antigen specificity and without framework and a method without a purpose.
Claim 16 and dependent claim thereof encompass a broad genus of antibodies comprising analog having up to 5% sequences modification in the VH of SEQ ID NO: 34 and 77 and VL of SEQ ID NO42 and 79 without antigen specificity and a method without a purpose.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of delivering/administering the antibody to a cancer overdressing PVR cells of a subject including melanoma, breast cancer . . . and lymphoma. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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.
At the bottom of page 5 of the specification discloses there are several methods known in the art for determining the CDR sequences of a given antibody molecule, but there is no standard unequivocal method. Determination of CDR sequences from antibody heavy and light chain variable regions can be made according to any method known in the art, including but not limited to the methods known as KABAT, Chothia and IMGT. A selected set of CDRs may include sequences identified by more than one method, namely, some CDR sequences may be determined using KABAT and some using IMGT, for example.
Example 2 of the specification is directed to generation and purification of anti-PVR mAbs. In order to generate anti-PVR antibodies, a recombinant protein was produced and purified,
hPVR-Fc, that combines extracellular part of human PVR and human Fc region of an
immunoglobulin G carrier as an immunogen. BALB/c mice were injected with 50 pg of the immunogen in complete Freund's adjuvant 5 and 2 weeks later in incomplete Freund's adjuvant. After 2 weeks, the sera were screened for the antibody titer. Four anti-PVR antibodies were generated. Of these, three antibodies were blocking anti-PVR mAbs, namely antibody 5B9 (also termed hPVR.09), antibody 7D4 (also termed hPVR.01) and antibody 4E5 (also termed hPVR.07). These antibodies all block TIGIT-Ig binding (as illustrated in Figures 3B-D, respectively). A fourth antibody was generated which does not block TIGIT-Ig
binding and was termed 2G3 (also termed hPVR.17) (Figure 3A).
Claims 1 and dependent claims thereof encompass the use of a abroad genus of antibodies comprising mixing 6 CDRs derived Kabat and IMAG system of antibodies 4E5 or 5B9 or 7D4 without antigen specificity and without framework a method without a purpose.
Claim 16 and dependent claim thereof encompass a broad genus of antibodies comprising analog having up to 5% sequences modification in the VH of SEQ ID NO: 34 and 77 and VL of SEQ ID NO42 and 79 without antigen specificity and a method without a purpose.
The claims recite CDRs without antigen specificity. There is unpredictability on how to screen for the missing framework of the antibody in the absence of the antigen specificity. The claims 16 and 18 encompass antibodies in which substitution, deletion and/or insertion in the CDR sequences of both the VH and VL regions of SEQ ID NOs: 34, 77, 42, 79. Neither the instant specification nor the prior art provide sufficient guidance or direction for one of ordinary skill in the art to make the antibodies encompassed by the breadth of the instant claims. 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 routinely 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"). 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 an antibody 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).
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. USA, 79(6):1979-1983, March 1982). Rudikoff et al teach 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. With respect to making the genus of antibodies using a set of particular VH CDRs or VL CDRs as the starting point, e.g., SEQ ID NOs: 36-38-40, 44-59-48. It’s known in the art that antibody-antigen affinity and specificity is a function of not only direct CDR to antigen interactions, but also the interactions of the CDRs with framework residues in the same chain, e.g., VH CDR binding to VH framework residues, and in the opposing chain, e.g., VH CDR binding to VL framework residues. In addition, the CDR residues of each chain can interact with the CDRs of the opposite chain. It is for this reason that antibody humanization protocols, e.g., humanization of a murine antibody, provide extensive guidelines as to the retention of certain murine residues in the context of the human framework so as to preserve this web of interactions, the loss of any one of these interactions having the potential to ablate antibody-antigen binding (see, e.g., Eduardo Padlan, Mol Immunol. 1994 Feb;31(3):169-217, in particular column bridging paragraph on page 177; page bridging paragraph pages 178-179 through page 180; pages 201, 204 and Tables 8, 22 and 23 and Adair et al., United States Patent No. 5,859,205, in particular columns 1-6, 9-11 and 27-28).
In the instant case, the claims 16 and 18 recite at least a portion of the 6 CDRs of a variable domain, not all the 6 CDRs or the variable domain itself. While claims 1 and dependent claims thereof recite antibodies comprising CDRs without framework and without epitope specificity and a method without a purpose. While CDRs are important for binding and contribute the majority of contact residues with the target antigen, the framework residues are also essential for maintaining the proper antigen-binding conformation of the CDRs and for proper association of the heavy and light chain variable regions. As such, it appears that making the claimed genus of antibodies would be an unpredictable endeavor requiring far more than routine experimentation because at least one CDR comprises less than a majority of the residues important for antigen recognition, let alone a single CDR. Moreover, art techniques for identifying other variable domains by screening require an intact variable domain comprising CDRs interspersed between frameworks as the starting structure to be taken through the screening assay. The instant claims recite less than this minimum structure that is required for screening, and the instant specification fails to provide sufficient direction or guidance as to the breadth of the frameworks that can accommodate the claimed CDRs while simultaneously providing appropriate structure to pair with a light chain variable domain capable of acting with heavy chain variable domain to create an antigen binding site. Thus, the minimal structure which the skilled artisan would consider predictive of the function of binding the antigen includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) from parental antibody 4E5, 5B9, 7D4 or 2G3 in the context of framework sequences which maintain their correct spatial orientation have the requisite antigen binding function. One of ordinary skill in the art could not predictably extrapolate the teachings in the specification, limited to antibodies that comprise both the heavy chain variable region and the light chain variable region or all six CDRs of 4E5, 5B9, 7D4 or 2G3 that binds the antigen to make and use antibodies that comprise portions of all six CDRs from parental antibody 4E5, 5B9, 7D4 or 2G3 i.e., antibodies comprising a heavy/light chain variable region each having less than the required full three CDRs as broadly as claimed. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required.
No common structural attributes identify the members of the structures of the antibody genus. Because the disclosure fails to describe the common attributes or characteristics that identify the antibody members of the genus, and because the genus is highly variant, CDRs alone is insufficient to describe the genus, even when considered in light of the general knowledge in the art concerning antibody. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus that the applicant was not in possession of the claimed genus. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
With respect to the recitation an antibody which does not comprise all 6 CDRs of the antibody 4E5, 5B9, 7D4 or 2G3, the Examiner directs Applicant's attention to the training material given by Bennett Celsa, Example 2: (Ab genus: modified CDR's) slides 34-40. Example 2 of the Training material which requires that the claims explicitly recite the binding antigen in addition to all 6 CDR regions for fulfillment of the written description requirements under § 112, 1. Slide 39 indicates that a claim encompasses antibodies with 6 intact CDRs as well as a subgenus of antibodies that encompass up to 10% variation (fragments and/or analogs) in the 6 CDRs lacks written description. Slide 40 provide the conclusion that, a single antibody species would not be deemed by one of skill in the art to be representative of a claim that defines an antibody that binds antigen X comprising at least 90% homology to the 6 CDR of the VH and VL chains.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
13. Claims 1-16 and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as containing 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 recite “delivering an isolated monoclonal antibody or an antibody fragment thereof to a cell comprising contacting the cell with the isolated monoclonal antibody or antibody fragment thereof” “wherein the cells are tumor cells” “comprising administering the isolated monoclonal antibody or antibody fragment thereof to cells of a subject”, “wherein the cells are of a cancer overexpressing PVR”, “wherein the cells are of a cancer selected from the group consisting of a melanoma, a breast cancer . . . and a lymphoma”. The claims are directed to methods without a purpose that fails to produce a tangible and technical result.
Example 13 of the specification tested the effect of the anti PVR mAbs on cytokine secretion using PBMC from healthy donors incubated with target cells in the present of antibodies (mKgG, 5B9mIgG, anti CTL-4 antibody, Ipi). The result shows induction of IFNγ secretion by anti-PVR mAbs indicates potential additional anti-tumorigenic effect of these compounds in cancer treatment.
Examples 11-12 of the specification are directed to prophetic example of in-vivo effect of anti-PVR antibodies on human tumor in a humanized mouse model-short/long term humanization.
Example 10 of the specification uses anti-PVR antibodies to reduce the survival of tumor cells in the absence of immune cells. The results shows that PVR blocking by 5B9 mAb significantly reduced viability of 20-40% compared to mIgG.
Example 8 shows that anti-PVR antibodies enhance T cell proliferation.
Claims 1-15 and 18, are not design to solve any desirable outcome, extolling benefits or features of the invention by delivering the claimed antibody. The claims fail to identify the condition or disorder that is being targeted for the antibody delivery.
The claims are directed to methods comprising delivering/contacting/administering specific monoclonal antibodies with unknown antigen target to a cell, including a tumor cell, a cell of a subject, a cancer cell overexpressing PVR or a cell derived from melanoma, breast cancer ovarian cancer, among others.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The instant claims are directed to a genus of use methods using antibodies that have no antigen target specificity, no activity, no purpose, no tangible or technical results.
To determine the broadest reasonable interpretation purpose of methods of delivering specific monoclonal antibodies to a cell comprising contacting the cell with the specific antibody, the method comprising administering the specific monoclonal antibody to cells or to a cell of a subject, including human subject, or cells are of a cancer overexpressing PVR or cells are of a cancer selected from the group consisting of a melanoma, a breast cancer among other, the specification is consulted.
The “correct inquiry in giving a claim term its broadest reasonable interpretation in light of the specification is . . . an interpretation that corresponds with what and how the inventor describes his invention in the specification, i.e., and interpretation that is “consistent with the specification.” In re Smith Int’l Inc., 871 F.3d 1375, 1375-1383 (Fed. Cir. 2017). The specification indicates that “use in inhibiting formation or distribution of metastases or reducing the total number of metastases in a subject” (page 24), “use in treating a viral infection”, “use in treating an angiogenesis-related disease or disorder” (page 25) and “method of treating cancer”, but the claims are not limited to these indications. Also, the limitations from the specification are int imported into the claims. SuperGuid Corp. v. DirectTV Enters., Inc., 358 F.3d 870, 875 (Fed. Cir. 2004).
The specification makes it clear that the essence of the invention is to treat cancer, inhibiting metastases, treating viral infection, treating an angiogenesis-related disease or disorder, treating cancer. Consistently, the claim preamble recites “ a method of delivering an isolated monoclonal antibody or an antibody fragment thereof to a cell comprising contacting the cell with the isolated monoclonal antibody or antibody fragment thereof, wherein the isolated monoclonal antibody”. None of the listed claimed antibodies were “delivered” /“administered” to a cell of subject including human to treat cancer, inhibiting metastases, treating viral infection, treating an angiogenesis-related disease or disorder, treating cancer.
The “multiple uses” claimed indicates that the unspecific antibodies have a multipurpose property that cannot be assigned to a single category due to the different uses of the property. The specification fails to demonstrate the claimed “multiple uses” of the claimed
antibodies can be administered to a cell of a subject, including human subject or the cells are of a cancer overexpressing PVR or to a melanoma cell or a breast cancer cell or an ovarian cancer cell among other. A person of ordinary skill in the art would not know, without
undue experimentation, which antibody would be effective for to achieve the claimed
multiple use methods. The Supreme Court’s 2023 decision in Amgen V. Sanofi which mainly involves the enablement requirement states that “where a patentee purports to invent an entire genus, it must enable the entire genus”, S. Ct.
All cells, and all cancers, in a subject as claimed, there are no examples provided by the specification. Note that determining the effects of the claimed antibodies in a cell line is not the equivalent to treatment of cancer of any type in a subject. Results obtained under controlled conditions and in inbred animals often differ from the clinical response obtained in patients. This applies in particular to strategies based on responses, including strategies drawn to cancer.
Given the relatively incomplete understanding in correlating in vitro assays and in vivo animal models to clinical treatment of cancer involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims, the claims are not enabled. See MPEP 2164.08.
If the use disclosed is of such nature that the art is unaware of successful treatments with chemically analogous compounds, a more complete statement of how to use must be supplied.
The determination that "undue experimentation" would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988).
The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements...However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims.” MPEP § 2164.03.
Further, in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297-1303 (CAFC 2005), the court states “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the 'inventor' would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis.”
The MPEP states that the issue of "correlation" is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. See MPEP 2164.02.
Claims 1-16 and 18 also encompasses a broad genus of monoclonal antibody comprising 6-CDRs but lack specific antigen to screen for the missing framework or a genus of antibodies comprising up to 5% modification in both the CDRs and/or framework.
This case is akin to the issue in Sanofi-Aventisub, the court relied on evidence showing that the
scope of the claims encompassed millions of antibodies and that it was necessary to screen each
candidate antibody in order to determine whether it met the functional limitations of the claim.
Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement.
While the specification in Amgen identified 26 exemplary antibodies that performed the claimed
function by their amino acid sequences, the claims at issue were directed to a class that included
“a `vast' number of additional antibodies” that Amgen had not described by their amino acid
sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire
class of antibodies by their function, which was much broader than the 26 exemplary antibodies
disclosed by their amino acid structure. In the instant case, the specification discloses 4 species
without defined characteristics. The instant claims are directed to a class of antibodies (lacking the antigen specificity and framework or comprising up to 5% modification) that included “a `vast' number of additional antibodies” that the instant specification fails to describe their amino acid sequences.
The claims simply direct skilled artisans to engage in the same iterative, trial-and-error process
the inventors followed to discover the antibodies would be delivered/administered to a cell, a cell of subject, tumor cells, cancer cell overexpressing PVR and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).”
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
14. No claim is allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 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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January 29, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644