Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendments and remarks filed 12-3-25 are acknowledged.
Claims 101, 102 and 104-110 are pending and under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 101, 102, 104-110 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.
At page 4-5 bridging paragraph applicant asserts the following (emphasis added):
“…the present specification provides adequate written support for the presently claimed invention by sufficiently disclosing both a representative number of species of the claimed genus, and structural feature common to the members of the genus. In particular, the specification discloses two variable heavy domain that have at least 90% sequence identity with
SEQ ID NO:244 (SEQ ID NO:218 and SEQ ID NO:244), and three variable light domain that
have at least 90% sequence identity with SEQ ID NO:256 (SEQ ID NO:222, SEQ ID NO:256
and SEQ ID NO:240). The present specification further discloses six antigen binding domains in
Figures 12 and 13 that are exemplary species of the ENPP3 binding domain of claim 101….”
Applicant's argument has been considered but has not been found convincing essentially for the reasons of record as described below.
The sequences applicant points to are not nearly sufficient to be representative of the claimed genus of ENPP3 binding domains.
As set forth at page 3 of the prior Office Action, “For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding, binding to a certain epitope), claiming antibodies with specific properties, e.g., ENPP3-binding, can result in a claim that does not meet written description even when the antigen(s) bound by the antibody is known because antibodies with those properties have not been adequately described. See Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).”
Note in this regard that according to the specification at para 0003, the ENPP3 protein “…has previously been reported to be highly expressed in renal cell carcinoma and
minimally expressed in normal tissue. In view of this, it is believed that anti-ENPP3
antibodies are useful, for example, for localizing anti-tumor therapeutics (e.g.,
chemotherapeutic agents and T cells) to such ENPP3 expressing tumors.” Thus, in order to make ENPP3 binding domain species representative of claimed genus said species must have the requisite structure (at least 90% sequence identity to each of SEQ ID NOs: 244 and 256), and must further be capable of localizing said binding domains to ENPP3 expressing tumors rather than, e.g., non-cancerous but ENPP3 positive tissues.
In this regard, the disclosed ENPP3 binding domain species which is XENP30262 (see para 0453 and Fig. 17C displaying Vh and Vl SEQ ID NOs: 486 and 488 which have at least 90% sequence identity to SEQ ID NOs: 244 and 256) exhibits very poor binding to ENPP3high KU812 cells (see Fig. 35) and this weak binding to ENPP3 expressing cells is reflected in the inability of XENP30262 to mediate redirected T-cell cytotoxicity (RTCC) of these same cells in vitro (see Fig. 42 and para 0461).
Similarly, the disclosed ENPP3 binding domain species which is XENP30821 (see para 00458 and Fig. 22C displaying Vh and Vl SEQ ID NOs: 534 and 536 which have at least 90% sequence identity to SEQ ID NOs: 244 and 256) and is also “ENPP3 low binding,” likewise very poorly mediates redirected T-cell cytotoxicity (RTCC) of KU812 cell in vitro (see Fig. 45). Additionally this ENPP3 binding domain species was shown to not suppress the growth of KU812 cells in vivo (see Figures 47, 50D and 50G).
Comparing the heavy and lights chains of the XENP30262 and XENP30821 antibodies to SEQ ID NOs: 244 and 256 of the instant claims the light chain CDR2 domain comprises a single amino acid change wherein “YASESIS” becomes “YESESIS.” (see below). The ordinarily skilled artisan would conclude that this single amino acid change in CDR2 is capable of generating species having structures that fall within the breadth of the claimed genus (the XENP30262 and XENP30821 antibodies), but that fail to bind ENPP3 to any useful extent, e.g., for localizing anti-tumor therapeutics (e.g., chemotherapeutic agents and T cells) to ENPP3-expressing cancer cells.
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Moreover, the XENP30262 and XENP30821 antibodies provide an example of a how “[a]ny number of Vh and VL CDR residues are expected, a priori, to contribute to ENPP3-binding and yet the instant specification and the knowledge in the art do not establish which residues of the disclosed Vh and VL CDRs that are structurally essential to ENPP3-binding versus those that are tolerant to change, and to what degree, i.e., conservative or radical.” (see prior Office Action at page 8, 1st paragraph).
However, the instant specification does not adequately describe how this single amino acid change in the Vl CDR2 region of SEQ ID NO: 256 causes the antibody to fail to bind ENPP3 to any useful extent, e.g., for localizing anti-tumor therapeutics (e.g., chemotherapeutic agents and T cells) to ENPP3-expressing cancer cells; nor does the specification teach how to avoid such mutations in the context of any of the other 27 amino acids that comprise the CDRs 1-3 of the SEQ ID NO: 256 Vl domain, or any of the other 34 amino acids that comprise the CDRs 1-3 of the SEQ ID NO: 244 Vh domain.
Furthermore, given the above the it appears that the teachings of the instant specification do not put the ordinarily skilled artisan in possession of a composition comprising an ENPP3 binding domain that comprises a variable heavy domain having SEQ ID NO: 218 or 244 and a variable light domain having SEQ ID NO: 240 since it appears that any ENPP3 binding domain having this particular light chain with a CDR2 domain comprising “YESESIS” will fail to bind ENPP3 to any useful extent, e.g., for localizing anti-tumor therapeutics (e.g., chemotherapeutic agents and T cells) to ENPP3-expressing cancer cells.
The undersigned agrees with applicant’s assertion that “…claim 101 is not exclusively claimed
functionally…;” however, as set forth in the prior Office Action at page 7, 1st paragraph, the issue remains that “the number of variants containing as many as 11+12=23 amino acid changes within the heavy and light chain CDRs of claim 101 is greater than (19)23 = 2.5 x 1029, which is many, many orders of magnitude more than the maximum estimated number of stars in the galaxy….,” and yet the specification fails to provide sufficient direction or guidance for the skilled artisan to know which species within this vast genus will bind ENPP3 to any useful extent, e.g., for localizing anti-tumor therapeutics (e.g., chemotherapeutic agents and T cells) to ENPP3-expressing cancer cells.
Applicant points to the teachings of the specification at para 0297 related to modification to the framework regions as part of their argument that the specification provides sufficient “guidance to a person of ordinary skill in the art as to where changes could be made in the amino acid of sequences enumerated in claim 101 without significantly impairing ENPP3 binding domain functionality,” but this is not material to the issue at hand and indeed the claims are not drawn to, e.g., an ENPP3 binding domains comprising the heavy chain CDRs of SEQ ID NOs: 245-247 and the light chain CDRs of SEQ ID NOs: 253-255. Indeed, if such a claim were present it would not be subject to a rejection under 35 USC § 112(a) because the ordinarily skilled artisan considering the teaching of the instant specification as of 3-1-19 in the context of their knowledge in the art would be deemed to be in possession of such a genus of ENPP3 binding domains.
With respect to applicant’s argument that the decision of the patent trial and appeal board (PTAB) in Ex parte Campbell (Appeal No. 2021-000865, July 20, 2021, hereinafter “Campbell”) provides an example of a situation where “…determined that the disclosure of US 15/661,658 (issued as US 11,396,550) provided adequate written description for claims that include VH/VL regions with 90% identity to known sequences, similar to the present claims,” is also not found convincing.
As a preliminary matter note that the decision in Campbell was a non-precedential decision and as such the BPAI finding in Campbell are binding only within that specific case but is not for other cases such as this one.
That said, by contrast to applicant’s argument and the Campbell decision the undersigned disagrees that “the possible substitutions are relatively small” as described above.
Applicant asserts the “…the present application specification discloses six representative species for the ENPP3 binding domains of claim 101,” pointing to “…six antigen binding domains in
Figures 12 and 13 that are exemplary species of the ENPP3 binding domain of claim 101.” (applicant’s emphasis shown).
For reference, said “six" binding domains of Figures 12 and 13 are portrayed below wherein the red arrow points to the Vh of SEQ ID NO: 244 and the blue arrow points to the Vl of SEQ ID NO: 256, and wherein the CDR1 / CDR2 / CDR3 domains are delineated with vertical lines:
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The skilled artisan understands that the specificity and affinity of an antibody for its cognate antigen is determined by the sequence and structure of the variable fragment (Fv) wherein antigen binding is primarily mediated by the complementarity determining regions (CDRs), and the framework residues are “…more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen,” see the teachings of Vajdos as set forth in the prior Office Action.
Thus, the art recognized that while the CDR residues of a given antibody are primarily responsible for its fine specificity, the overall structure of the variable domain is dependent on the framework regions providing the supporting structure for the CDR loops. Note in this regard that even seemingly minor framework amino acid differences can substantially affect the overall structure, i.e., changes to the framework residues can have effects on the positioning of the CDR loops. For example, see Vajdos at page 422, last full sentence of the left column: “The only difference in the light chain frameworks occurs at position 66, where an arginine in Fab4D5v4 is substituted by a glycine in Fab2C4, causing the polypeptide backbone to undergo a significant rearrangement.”
Considering the above, applicant’s argument that the “specification discloses six representative species for the ENPP3 binding domains of claim 101” is not found convincing because it is inconceivable how such species could be said to be representative of the claimed genus given the possible variability encompassed by the instant claims (see above) and further given the importance of the CDR regions for mediating ENPP3-binding affinity sufficient to allow for localizing anti-tumor therapeutics (e.g., chemotherapeutic agents and T cells) to ENPP3 expressing cancer cells.
In conclusion, given the above the skilled artisan cannot extrapolate from the disclosure of the instant specification to establish possession of the breadth of ENPP3-binding domains encompassed by the instant claims.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of antibody-like binding molecules because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of ENPP3-binding domains.
Claims 101, 102, and 104-110 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 composition comprising an ENPP3 binding domain comprising the variable heavy and light domains having SEQ ID NOs: 244 and 256; or SEQ ID NOs: 244 and 222; or SEQ ID NOs: 218 and 256; or SEQ ID NOs: 218 and 222, does not reasonably provide enablement for the breadth of the instant claims as they encompass the genus of any ENPP3 binding domain comprising any variable heavy domain having at least a 90% sequence identity to SEQ ID NO: 244 and a variable light domain having at least a 90% sequence identity to SEQ ID NO: 256.
As described above, according to the specification at para 0003, the ENPP3 protein “…has previously been reported to be highly expressed in renal cell carcinoma and minimally expressed in normal tissue. In view of this, it is believed that anti-ENPP3 antibodies are useful, for example, for localizing anti-tumor therapeutics (e.g., chemotherapeutic agents and T cells) to such ENPP3 expressing tumors.” Thus, in order to make ENPP3 binding domain species representative of claimed genus said species must have the requisite structure (at least 90% sequence identity to each of SEQ ID NOs: 244 and 256), and must further be capable of localizing said binding domains to ENPP3 expressing tumors rather than, e.g., non-cancerous but ENPP3 positive tissues.
In this regard, the disclosed ENPP3 binding domain species which is XENP30262 (see para 0453 and Fig. 17C displaying Vh and Vl SEQ ID NOs: 486 and 488 which have at least 90% sequence identity to SEQ ID NOs: 244 and 256) exhibits very poor binding to ENPP3high KU812 cells (see Fig. 35) and this weak binding to ENPP3 expressing cells is reflected in the inability of XENP30262 to mediate redirected T-cell cytotoxicity (RTCC) of these same cells in vitro (see Fig. 42 and para 0461).
Similarly, the disclosed ENPP3 binding domain species which is XENP30821 (see para 00458 and Fig. 22C displaying Vh and Vl SEQ ID NOs: 534 and 536 which have at least 90% sequence identity to SEQ ID NOs: 244 and 256) and is also “ENPP3 low binding,” likewise very poorly mediates redirected T-cell cytotoxicity (RTCC) of KU812 cell in vitro (see Fig. 45). Additionally this ENPP3 binding domain species was shown to not suppress the growth of KU812 cells in vivo (see Figures 47, 50D and 50G).
Comparing the heavy and lights chains of the XENP30262 and XENP30821 antibodies to SEQ ID NOs: 244 and 256 of the instant claims the light chain CDR2 domain comprises a single amino acid change wherein “YASESIS” becomes “YESESIS.” (see below). The ordinarily skilled artisan would conclude that this single amino acid change in CDR2 is capable of generating species having structures that fall within the breadth of the claimed genus (the XENP30262 and XENP30821 antibodies), but that fail to bind ENPP3 to any useful extent, e.g., for localizing anti-tumor therapeutics (e.g., chemotherapeutic agents and T cells) to ENPP3-expressing cancer cells.
Thus, the skilled artisan is not enabled to make use the breadth of claimed antibodies as they encompass, e.g., the species of ENPP3 binding domains that comprise a light chain variable region of SEQ ID NO: 240.
Likewise, for the same reasons that the teachings of the instant specification are said to be insufficient to put the skilled artisan in possession of the claimed genus of ENPP3-binding domains, the teachings of the instant specification are likewise provide insufficient direction or guidance as to which particular species encompassed by the vast breadth of ENPP3-binding domains of the instant claims will be able to successfully bind to ENPP3 with sufficient affinity to permit localization of anti-tumor therapeutics (e.g., chemotherapeutic agents and T cells) to ENPP3-expressing cancer cells, e.g., in the context of a patient having ENPP3-expressing renal cell carcinoma.
In sum, in view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trial and error experimentation to practice the claimed invention.
Claims 101-106 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 85 and 88 of copending application no. 18634868 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because multiple VH and VL sequences shown in reference Figure 22 are identical to the heavy and light chain variable domains recited in the instant claims and thus the anticipate the composition of the instant claims. Note that while reference claim may not explicitly recite “a composition,” in making such the antibody of the reference claims the skilled artisan would be making a “a composition” of antibody in an aqueous solution. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims.
Applicant requests that the above rejection “…be held in abeyance until the other remaining
rejections have been resolved,” pointing to MPEP §808 I.B. l .(i). Applicant’s request is acknowledged, but cannot be granted. Obviousness type double patenting rejections, whether provisional or not, cannot be held in abeyance. A double patenting rejection can be overcome, e.g., by a convincing rebuttal of the merits of the rejection, by amending the claims such that they are no longer anticipated and/or rendered obvious by the reference claims or by filing a proper terminal disclaimer.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Daniel E Kolker can be reached at 571-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644