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 remarks and amendments filed 8-1-25 are acknowledged.
Claims 1, 7-36, 40 and 44 are pending.
Your examiner at the USPTO has changed.
Upon reconsideration the species of target for the first binding domain has been extended to include PD-L1.
The prior rejections under 35 USC § 112(b) and 103 have been withdrawn upon reconsideration.
New Grounds of Rejections based, in part, on this new species of target and further due to reconsideration of the prior Office Action are set forth below.
Claims 1, 7-15, 18-36, 40 and 44 and under examination as they read on the elected species of
specific target for the first binding domain which is PD-1 or PD-L1;
specific target for the second binding domain which is VEGF;
specific heavy chain variable region sequence which is SEQ ID NO: 64;
specific light chain variable region sequence which is SEQ ID NO: 65;
specific VH CDR1, 2, and 3 sequences which are SEQ ID NOs: 34, 39, and 44 (Nivolumab);
specific VL CDR1, 2, and 3 sequences which are SEQ ID NOs: 49, 54, and 59 (Nivolumab);
corresponding IgG identity of Nivolumab;
specific peptide linker sequence which is (GGGGS)3; AND
specific heavy chain sequence which is SEQ ID NO: 70.
Claims 16-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/23/2024.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 9-15 and 18-26 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.
Claim 7 recites: “The fusion protein according to claim 1, wherein the first binding domain and the receptor or ligand are selected from the following combinations:
(1) the first binding domain targets and binds to PD-L1, and the receptor or ligand is selected from TGF-βRII, VEGFR…or
(2) the first binding domain targets and binds to PD-1, and the receptor or ligand is selected from human CD80, CD86, VEGFR…or (3) the first binding domain targets and binds to CTLA-4….”
Claim 9 recites: “The fusion protein according to claim 7, wherein
the first binding domain targets and binds to PD-L1;
the second binding domain is a fragment of human TGF-βRII; or
the first binding domain targets and binds to PD-1, and the second binding domain is selected from human CD80 ECD, CD80IgV region, human CD80IgVIgC, VEGFRI ECD, VEGFR2 ECD or a combination of the second extracellular region of VEGFRI and the third extracellular region of VEGFR2; or
the first binding domain targets and binds to Claudin 18.2, HER-2 or EGFR, and the second binding domain is selected from human CD80 ECD, CD80IgV region, human CD80 IgVIgC, VEGFR1 ECD, VEGFR2 ECD or a combination of the second extracellular region of VEGFR1 and the third extracellular region of VEGFR2.”
It would be unclear to the ordinarily skilled artisan precisely what is encompassed in the breadth of claim 9. Some of ordinary skill in the art would interpret the phrase “The fusion protein according to claim 7, wherein the first binding domain targets and binds to PD-L1; the second binding domain is a fragment of human TGF-βRII; or the first binding domain targets and binds to PD-1, and the second binding domain is selected from human CD80 ECD….” to mean that in one embodiment the fusion protein according to claim 7 comprises a first binding domain targets that binds to PD-L1; or in another embodiment the fusion protein according to claim 7 comprises a second binding domain which is a fragment of human TGF-βRII; or in another embodiment the fusion protein according to claim 7 comprises a first binding domain targets and binds to PD-1, and a second binding domain which is “selected from human CD80 ECD….” However, others of ordinary skill in the art would construe the language of this claim to imply that in one embodiment the fusion protein according to claim 7 comprises a first binding domain targets that binds to PD-L1 AND further comprises a second binding domain which is a fragment of human TGF-βRII; or in another embodiment the fusion protein according to claim 7 comprises a first binding domain targets and binds to PD-1, and a second binding domain which is “selected from human CD80 ECD….”
Given these different possible interpretations, each of which require certain assumptions be made about the language being used, the skilled artisan would not clearly understand the metes and bounds of claim 9 and dependent claims thereof. However, for examination purposes claim 9 will be considered as if it encompasses in its breadth the elected species of fusion protein wherein the specific target for the first binding domain which is PD-1 or PD-L1, and the specific target for the second binding domain which is VEGF.
In addition with respect to claim 14 which recites: “[t]he fusion protein according to claim 13, wherein the amino acid sequences of CDRs 1-3 of the heavy chain variable region are SEQ ID NOs: 3, 8, 13; and/or an amino acid sequence of CDRs 1-3 of the light chain variable region are SEQ ID NOs: 18, 23, 28,” it would unclear to the ordinarily skilled artisan if claim 14 should be interpreted to limit said fusion protein according to claim 13 to ONLY the particular member of parent claim 13 that encompasses these sequences, i.e., “(3) the amino acid sequences of CDRs 1-3 of the heavy chain variable region are SEQ ID NOs: 3, 8, 13, or an amino acid sequence having 1 or 2 amino acid substitutions on SEQ ID NOs: 3, 8, 13; and/or an amino acid sequence of CDRs 1-3 of the light chain variable region are SEQ ID NOs: 18, 23, 28, or an amino acid sequence having 1 or 2 amino acid substitutions on SEQ ID NOs: 18, 23, 28,” as opposed to claim 13, parts (1),(2),(4) and (5), OR if claim 14 should be interpreted to be limited to ONLY THE fusion protein comprising “the amino acid sequences of CDRs 1-3 of the heavy chain variable region which are SEQ ID NOs: 3, 8, 13, without any amino acid substituions to each; and/or an amino acid sequence of CDRs 1-3 of the light chain variable region which are SEQ ID NOs: 18, 23, 28, without any amino acid substituions to each.” Since different skilled artisans would have different understandings as to the metes and bounds of this claim its meaning is indefinite.
Moreover, given this uncertain as to the metes and bounds of claim 14, dependent claims 15 is similarly indefinite and rejected for substantially the same reasons.
Furthermore, claim 21 is also rejected by virtue of the same reasoning as set forth for claim 14. Moreover, given this uncertain as to the metes and bounds of claim 21, dependent claims 22-26 are similarly indefinite and rejected for substantially the same reasons.
For examination purposes, claims 14, 21 and dependent claims thereof will be examined as if they encompass in their breadth antibodies having Vh CDR sequences having 1 or 2 amino acid substitutions relative to the recited CDRs identified by SEQ ID NOs. and/or having Vl CDR sequences having 1 or 2 amino acid substitutions relative to the recited CDRs identified by SEQ ID NOs.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 7-10, 28-32, 35, 40 and 44 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Feng et al. (WO2020135556, cited herewith), which was the basis for the United States National Phase entry published as US20220073620, cited herewith, hereinafter “Feng.”
All references to the teachings of Feng refer to the English language equivalent of the ‘556, i.e., refer to the teachings of the ‘620.
Feng teaches an “…antibody fusion protein with FTF structure has an amino acid sequence of heavy chain as shown in SEQ ID NO: 5, and an amino acid sequence of light chain as shown in SEQ ID NO: 9….,” wherein SEQ ID NOs: 5 and 9 form an antibody fusion protein that binds a first antigen which is “hPD-L1” and a second antigen which is “hVEGF-A,” wherein said antibody fusion protein is referred to as “FTF” or “H2L2” (see Fig. 2; paras 56-57; 104; 137; Table 1 and claim 3).
The amino acid sequence of Feng SEQ ID NO: 5 (H2) is shown aligned to SEQ ID NO: 70 of the instant claims below, wherein a “Trap binding to human VEGF-A” (see Feng at para 135 and SEQ ID NO: 1, enclosed in a rectangle below) has been inserted into the IgG1 hinge region of SEQ ID NO: 5, “…EPKSC-GS linker-Trap-GS linker-DKTHTCPPCPA….”:
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Finally, at paras 68-69 and 126 Feng teaches pharmaceutical composition comprising their antibody fusion proteins and kits comprising antibody fusion proteins. Note in this regard that teaching a kit will anticipate “[a] diagnostic kit comprising…” as recited in claim 44 since this preamble language merely recites the purpose or intended use of the kit but has no apparent meaning as to the claimed invention’s limitations (see MPEP § 2111.02(II)).
Thus, the Feng teaches an antibody fusion protein that binds a first antigen which is “hPD-L1” and a second antigen which is “hVEGF-A” which has a structure that anticipates the instant claims.
Claims 1, 7-15, 28-32, 35, 40 and 44 are rejected under 35 U.S.C. 103 as being obvious over Feng et al. (WO2020135556, cited herewith), which was the basis for the United States National Phase entry published as US20220073620, cited herewith, hereinafter “Feng,” in view of Fang et al. (WO2021037007, cited herewith), which was the basis for the United States National Phase entry published as US 20220177590, cited herewith, hereinafter “Fang.”
All references to the teachings of Fang refer to the English language equivalent of the ‘007, i.e., refer to the teachings of the ‘590.
The applied reference has a common inventor with the instant application, and may have common assignee. Based upon the earlier effectively filed date of the reference it at least constitutes prior art under 35 U.S.C. 102(a)(2). Moreover, dependent on the effective filing date of the claimed invention (which cannot be accurately ascertained in the absence of an English language translation of CN202010199036.2), the teachings of Fang may also be prior art under 35 U.S.C. 102(a)(1).
Insofar as applicant can establish that Fang et al. (WO2021037007) is not valid prior art under 35 U.S.C. 102(a)(1), this rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
The teachings of Feng are given above.
However, Feng fails to teach an antibody fusion protein with an FTF structure that comprises the particular PD-L1 heavy and light chains recited in claims 11-15.
Fang teaches the production of an anti-PD-L1 antibody comprising heavy and light chains designated “hAAG5D8.” (see Example 1). SEQ ID NOs: 31 and 32 of Fang are identical to SEQ ID NOs: 66 and 67 encompassed in the breadth of claims 11-15. The ability of the hAAG5D8 anti-PD-L1 antibody to control the growth of murine colorectal cancer cells in an vivo model as compare to “MPDL3820A.” i.e. the well-known anti-PD-1 antibody “Atezolizumab,” was compared in Example 6 where it was shown that “…that hAAG5D8 at a concentration of 3 mg/kg or above has a significant tumor inhibitory effect on subcutaneously transplanted tumors of mouse colorectal cancer. At the dose of 3 mg/kg, the tumor inhibitory effect of the anti-PD-LI antibody has been significantly superior to that of Atezolizumab.” (see para 77; Fig. 5 and Table 11).
Given the reference teachings it would have been obvious to one of ordinary skill in the art that the “hAAG5D8” anti-PD-L1 Vh and Vl chains of Fang (Fang SEQ ID NOs: 31 and 32) could be substituted for the anti-PD-L1 Vh and Vl chains of SEQ ID NOs: 5 and 9 of Feng with an expectation that that the “hAAG5D8” anti-PD-L1 Vh and Vl chains of Fang will provide adequate PD-L1 binding and neutralization capacity. A reason the ordinarily skilled artisan would have been motivated to use the “hAAG5D8” anti-PD-L1 Vh and Vl chains of Fang in place of the anti-PD-L1 Vh and Vl chains present in the FTF/H2L2 of Feng was because Fang demonstrated that antibodies comprising their “hAAG5D8” anti-PD-L1 Vh and Vl chains (i) “…bind[] to PD-Ll with extremely high specificity” (see para 67), and (ii) demonstrate that antibodies comprising their “hAAG5D8” anti-PD-L1 Vh and Vl chains outperform an art-recognized, clinically tested anti-PD-L1 inhibitor, Atezolizumab.
With such a substitution, the ordinarily skilled artisan would be producing a fusion protein that renders the fusion proteins of claims 11-15 prima facie obvious.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 1, 7-10, 18-32, 35, 40 and 44, are rejected under 35 U.S.C. 103 as being obvious over Feng et al. (WO2020135556, cited herewith), which was the basis for the United States National Phase entry published as US20220073620, cited herewith, hereinafter “Feng,” in view of Hu et al. (20220106389, cited herewith), Nakhoda et al. (Pharmaceutical Medicine (2020) 34:83–91, cited herewith), Shah et al. (Human Vaccines & Immunotherapeutics, 2018, VOL. 14, NO. 2, 269–276, cited herewith).
The teachings of Feng are given above.
However, Feng fails to teach an antibody fusion protein with an FTF structure that comprises a PD-1 binding domain, such as the particular PD-1 binding domains recited in claims 18-27 in lieu of the particular PD-L1 binding domain of the FTF.
Hu teaches that Nivolumab from Briston-Myers Squibb and VEGF-Trap by Sanofi-Aventis had been used in the art to treat cancer (See para [0008] and claim 13).
Moreover, Nakhoda teaches that while PD-L1 and PD-1 inhibitors have been successfully used to treat a number of different cancers (see, e.g., at page 84, two full paragraphs), each of these treatment strategies have failed in some instances: “For example, in patients with advanced urothelial carcinoma, atezolizumab showed no improvement in OS over chemotherapy in patients with platinum refractory disease with PD-L1 overexpression, despite phase II evidence
revealing an improved overall response rate when compared with historical controls [48, 49]. Similarly in small-cell lung cancer (SCLC), nivolumab gained accelerated FDA approval
for advanced disease that had progressed on platinum-based therapy based on phase I/II studies and a randomized expansion cohort that revealed an overall response rate of 10%
with nivolumab monotherapy and a 23% response rate in the nivolumab/ipilimumab combination group [44]. However, a phase III study of single-agent nivolumab failed to improve survival over chemotherapy in the second-line setting [50]. Additionally, combination nivolumab/ipilimumab failed to show efficacy as maintenance therapy after first-line chemotherapy in SCLC [51].”
(see page 86-87 bridging paragraph).
Given the variable success observed with each of PD-1 and PD-L1 inhibition, the ordinarily skilled artisan would not be surprised by the Conclusion statement of Nakhoda which emphasizes the importance of careful evaluation of these therapeutics across a variety of cancer types:
“The human immune response is highly regulated and involves complex interactions of agonists and antagonists. While we have witnessed great success and broad applicability of immunotherapeutics, there have likewise been a number of disappointing results secondary to a failure to translate encouraging preclinical and early clinical data into phase III trials. Unfortunately, numerous factors significantly impede our full understanding of the immune system and its interaction with tumors. These include but are by no means limited to theoretical ADA effects, suboptimal biologic doses, resistance mechanisms, and the dynamic nature of the
TME. The success of late phase clinical trials relies on optimizing preclinical and early clinical studies to identify key on-target and off-target effects, dosing, and pharmacologic properties. Associated biomarker identification can significantly contribute to the selection of tumor types in which these agents are successful. Combination immunotherapeutic regimens require careful safety analysis as clinically significant improvements in efficacy may not always outweigh
the harm associated with cumulative toxicity. Ultimately, the future of the immunotherapeutic armamentarium will depend on a more measured approach in early clinical trials while we continue to unravel the mysteries of the TME in preclinical studies.” (see page 88-89 bridging paragraph).
While Nakhoda does not discuss the reasons that anti-PD-1 and anti-PD-2 may have differing effects in different cancer types, as discussed by Shah in the col. bridging paragraph on page 269, the PD-L1 and PD-L2 ligands of PD-1 are expressed on different cell types and have different biological activities:
“PD-1 is a member of the CD28 immunoglobulin family expressed by CD4C and CD8C T cells4 that interacts with ligands in the B7 family, PD-L1 and PD-L2. PD-L1 (B7-H1, CD274) is a type 1 transmembrane protein expressed on tumor cells, antigen presenting cells (APCs) including dendritic cells, macrophages and B cells, and activated T cells. PD-L2 (B7-DC, CD273) expression, however, is limited to APCs. The interaction of PD-1 with PD-L1 suppresses T
cell proliferation and cytokine secretion,5 inhibiting late phase immune responses.4,6 Monoclonal antibodies targeting PD-1 can facilitate an anti-tumor immune response and have demonstrated durable responses in a variety of cancer types.7–14 Antibodies that target PD-L1 would preserve the interaction between PD-1 and its other ligand, PD-L2. PDL2 may play a role in immune tolerance and effector T cell response.6 Differences between targeting PD-1 and PD-L1
are of unclear significance, as PD-1 inhibitors have not been directly compared to PD-L1 inhibitors.”
When the above teachings are taken together, it is apparent that it would have been obvious to one of ordinary skill in the art that use of a PD-1 binding domain in place of the PD-L1 binding domain of the antibody fusion protein with FTF structure of Feng. A reason the ordinarily skilled artisan would have been motivated to substitute a PD-1 binding domain for the PD-L1 binding domain of the antibody fusion protein with FTF structure of Feng was because, the ordinarily skilled artisan would understand from the teachings of Nakhoda and Shah that (i) numerous factors significantly impede our full understanding of the immune system and its
interaction with tumors, and (ii) anti-PD-1 and anti-PD-L1 antibodies have substantially different mechanisms of action, and thus it would be difficult for the ordinarily skilled artisan to predict, a priori, if any given cancer will respond better to an PD-1 or PD-L1 inhibitor. In light of this, it would be obvious to one of ordinary skill in the art to also make a PD-1 binding/inhibiting antibody fusion protein with the FTF structure of Feng. As to the particular PD-1 binder/inhibitor, it would have been obvious to one of ordinary skill in the art to substitute the variable domains of the nivolumab antibody for the variable domain of the anti-PD-L1 antibody present in SEQ ID NOs: 5 and 9 of Feng given the wide spread success of this antibody in treatment various cancers as set forth by Nakhoda. In so doing, the ordinarily skilled artisan will produce antibodies comprising the various sequences recited in claims 18-27.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Applicant’s Remarks at pages 15-16
Applicant’s arguments, insofar as they are relevant to the New Grounds of Rejection under 35 USC § 103 set forth above are addressed below.
Applicant’s first argument that would be relevant to the obviousness rejections set forth above is that, “[t]he presently claimed bi specific fusion protein achieves significantly advantageous improvement of expression. As demonstrated in Table 6 of Example 2, compared with the corresponding control protein, the presently claimed Hibody bispecific fusion proteins Hib-PLT, Hib-PDC, and Hib-PDV increase the expression levels by 52.85%, 33.43% and 25.6% respectively. That effect is very significant and was unexpected.”
Applicant's argument has been considered but has not been found convincing for the reasons described below.
Given that the elected species of specific target for the second binding domain is VEGF, wherein the specific heavy chain sequence is SEQ ID NO: 70 (which comprises the VEGF binding domain of SEQ ID NO: 33), the relevant comparator is the “Hib-PDV” bispecific antibody in Table 6 which demonstrated an increased expression compared to “Control protein 3”:
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Applicant’s argument that the observed increase in expression was “very significant and was unexpected” and therefore “the presently claimed fusion proteins are non-obvious” has been considered but is not convincing.
As part of Example 1 at page 27 the specification teaches “Control proteins 1-3: constructed according to the bifunctional molecular structure in WO2015/l18175.”
A copy of Lo et al., WO2015l18175, hereinafter “Lo,” is cited herewith.
According to Lo at paragraph 0001, “This invention relates generally to bifunctional molecules including (a) a TGFβRII or fragment thereof capable of binding TGFβ and (b) an antibody, or antigen binding fragment thereof, that binds to an immune checkpoint protein, such as Programmed Death Ligand 1 (PD- Ll), uses of such molecules (e.g., for treating cancer), and methods of making such molecules.”
Figure 1 of Lo is as follows:
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Lo does not mention VEGF, thus for examination purposes it will be assumed that “Control protein 3” joins a “Second binding domain fragment” which is “The combination of the extracellular region ofVEGFR1 and the (GGGGS)3 third extracellular region of VEGFR2” to the C-terminus of an anti-PD-1 antibody which lacks the hinge region insert present in Hib-PDV. Note however that this is all based on assumption as nowhere does the specification appear to explicitly describe the precise structure of “Control protein 3.”
That said, assuming “Control protein 3” has the structure postulated above, it is the opinion of the undersigned that the ordinarily skilled artisan would not necessarily consider the increased expression of Hib-PDV shown in Table 6 to be “very significant and unexpected” because the ordinarily skilled artisan would expect antibodies having very different structure to exhibit different expression levels. Note in this regard that as set forth in MPEP § 716.02(e), applicant “must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness.”
Applicant further argues the following (applicant’s emphasis shown):
“There is also a substantial improvement in binding activity (binding force). As confirmed
in Table 7 of Example 3, compared with the corresponding control protein, the binding activities
of the presently claimed Hibody bispecific fusion protein Hib-PLT, Hib-PDC, and Hib-PDV are
respectively 70 times, 35311 times and 2 times higher than that of the control. It can be seen that
the binding activities of Hib-PLT, Hib-PDV and Hib-PDC constructed by the double antibody
model provided by the present application are all greatly improved, which is superior in binding
activity to its monomeric counterparts.”
Applicant’s argument has been considered but has not been found convincing because, as stated above, MPEP § 716.02(e) instructs that applicant “must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness” and yet nowhere does the specification appear to explicitly describe the precise structure of the “VEGFR-His” protein of Table 7 which has an EC50 value 35K greater than that of “Hib-PDV.” For example does the “VEGFR-His” protein comprising the VEGFR transmembrane domain? What evidence is there that the “VEGFR-His” protein is properly folded and soluble?
Moreover, the “VEGF-Trap” of Holash et al. (Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11393-8, cited herewith), upon which the structure of SEQ ID NO: 33 appears to be based, (“VEGF-TrapR1R2 was created by fusing the second Ig domain of VEGFR1 with the third Ig domain of VEGFR2” at page 11393-94 bridging paragraph) is itself a very high affinity binder, “To determine binding affinity of the Traps for VEGF, equilibrium binding assays were performed in which different concentrations of the Traps were incubated with VEGF165, and the amount of unbound VEGF165 was measured, revealing that…VEGFTrapR1R2 has a binding affinity of about 1 pM (Fig. 2A).” Thus, the ordinarily skilled artisan would have reasonably expected Hib-PDV to bind to plate bound VEGF with perhaps even greater affinity than that displayed in Table 7 of the instant specification when considering the teachings of Holash. Moreover, insofar as the “VEGFR-His” of Table 7 is presumably properly folded and soluble, it is noted that it would still not be expected to exhibit substantial VEGF binding unless it also is capable of forming a dimer since such is required for simultaneous interaction at both binding faces of the VEGF homodimer as described by Stefano et al. (Bioconjug Chem. 2012 Dec 19;23(12):2354-64, cited herewith) at page 2361 col. bridging paragraph.
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 11-15 and 18-22 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, e.g., the fusion proteins of claims 23-26 wherein the PD-1 binding fusion proteins have at least the six sequence defined, invariant CDRs, three from a VH and three from a VL, does not reasonably provide enablement for PD-L1 and PD-1-binding fusion proteins comprising, e.g., a “first binding domain targets and binds to PD-L1, and the CDRs of the heavy chain variable region and/or the CDRs of the light chain variable region in the Fab of the IgG have the same CDR sequence as the antibody defined by the following sequence… wherein the antibody is defined as follows: (1) the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 66; and/or (2) the amino acid sequence of the light chain variable region is shown in SEQ ID NO: 67 (claim 11); or for example a “first binding domain targets and binds to PD-1, and the CDRs of the heavy chain variable region and/or the CDRs of the light chain variable region in the Fab of the IgG have the same CDR sequence as the antibody defined by the following sequence…wherein the antibody is defined as follows: (1) the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 64; and/or (2) the amino acid sequence of the light chain variable region is shown in SEQ ID NO: 65.” (claim 18).
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
When it comes to the many variant antigen binding domains encompassed by the instant claims, neither the teachings of the prior art nor the instant specification provide sufficient direction or guidance for the skilled artisan to make the breadth of PD-L1 and PD-1 binding domains encompassed by the instant claims in the absence of undue experimentation.
The instant claims encompass in their breadth PD-L1 and PD-1 binding domains having any heavy chain comprising various sequence specified CDR 1-3 regions OR any light chain comprising various sequence specified CDR 1-3 regions.
It is 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)(both cited herewith).
It is also known that given one specified variable domain, either heavy or light, the skilled artisans can screen libraries to identify other variable domains that will pair with the starting variable domain and maintain antigen specificity (Portolano et al., J Immunol. 1993 Feb 1;150(3):880-7, see entire document, particularly figure 1, cited herewith). Thus, it is known in the art that artisans can screen for other variable domains that will ensure a functional antibody of defined antigen specificity if a full variable domain is used in the screening assay.
Thus, based on the knowledge in the art, the skilled artisan understands that 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, making the claimed genus of antibodies would be an unpredictable endeavor requiring far more than routine experimentation because the isolated CDR1-3 sequences of a heavy or light chain variable region of an antibody comprises less than a majority of the residues important for antigen recognition. Moreover, enabled prior art techniques for identifying other variable domains by screening make use of 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 Vh/Vl frameworks that can accommodate the claimed CDRs while simultaneously providing appropriate structure to pair with the cognate Vl/Vh chain to create the genus of antibodies that can bind PD-L1 or PD-1.
When the above is considered together it is evident that undue trial and error experimentation would be required of the skilled artisan to probe the genus of sequences encompassed by the instant claims to determine which are capable of encoding heavy and/or light chain variable domains capable of forming an antibody that can bind PD-L1 or PD-1.
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, undue experimentation would be required to practice the claimed invention commensurate with the scope of the claims.
A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentech, Inc, v. Novo Nordisk, 42 USPQ 2d 1001,(CAFC 1997), the court held: “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable” and that “[t]ossing out the mere germ of an idea does not constitute enabling disclosure”. Further, “[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement”.
Thus, the instant specification provides insufficient teachings or objective evidence to guide the skilled artisan to make and use the antibodies encompassed by the breadth of the instant claims. Rather, the instant claims encompass an invention of tremendous scope, and essentially calls for trial and error by the skilled artisan to begin discovering the claimed invention without assisting the skilled artisan in such an endeavor, which does not constitute adequate enablement.
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 11-15 and 18-26 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. This is a written description rejection.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
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., PD-L1 and PD-1-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).
Along these same lines, as more recent Federal Circuit decision, Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), describes how when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself not just a description of the sequence to which the antibody binds. Amgen, 872 F.3d at 1378-79.
The importance of this court decision was expounded upon by Robert W. Bahr, Deputy Commissioner for Patent Examination Policy in a memorandum clarifying the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) as it relates to claims drawn to antibodies (see Memorandum of February 22, 2018, 2 pages, available at https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf). Bahr’s memo describes how the so-called “newly characterized antigen” test, which was based on an example in previously issued USPTO training materials and had been used in the past for determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody, is defunct. The Memorandum explains that USPTO personnel should continue to follow the relevant sections of the MPEP pertaining to the written description requirement of 35 U.S.C. § 112(a), except insofar as the MPEP indicates that disclosure of a fully characterized antigen may provide written descriptive support of an antibody to that antigen.
In particular, MPEP § 2163 instructs 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 claimed genus…See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").”
Note well: even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
In the instant case, the claims are drawn to “Hibodies” comprising anti-PD-L1 and anti-PD-1 antibodies comprising Vh and Vl CDRs having up two amino acid substitutions per CDR. For example, in the case of the anti-PD-L1 antibody comprising the Vh and Vl CDRs of SEQ ID NOs: 1,6,11 and 16,21,26 (see claim 13(1)) this amounts to a total of 53 amino acid residues across the six CDRs, and after incorporating up to 12 total substitutions this amounts to ≈ 5.9 x 1026 variants which is many, many orders of magnitude more than the maximum estimated number of stars in our galaxy (≈1-4 x 1011, see, e.g., https://www.space.com/25959-how-
many-stars-are-in-the-milky-way.html). Similar results would be expected for each of the claimed anti-PD-1 and anti-PD-L1 Hibody CDRs having 1-2 amino acid substitutions per CDR.
Thus, the breadth of the claimed genus is enormous encompassing antibodies having any number of amino acid substitutions, insertions or deletions to the CDR domains, be they radical or conservative.
However, simply reciting a structure, e.g., anti-PD-L1 and anti-PD-1 antibodies comprising certain sequence specified Vh and Vl CDRs having up two amino acid substitutions per CDR, be they radical or conservative, and its function, i.e., binding to PD-L1 or PD-1, respectively, provides insufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995).
Conservation of the CDR residues is of particular importance because any number of Vh and VL CDR residues are expected, a priori, to contribute to antigen binding and yet the instant specification and the knowledge in the art do not establish which residues of the claimed PD-L1 and PD-1 binding antibodies are structurally essential to antigen binding versus those that are tolerant to change, and to what degree, i.e., conservative or radical.
To illustrate this point, consider Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28, cited herewith) which teaches “[t]he specificity and affinity of an antibody for its cognate antigen is determined by the sequence and structure of the variable fragment (Fv): a heterodimer consisting of the N-terminal domains of the heavy and light chains. Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains 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. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.” (see, page 416, column bridging paragraph, emphasis added).
Vajdos goes on to teach that "[b]y analyzing panels of point mutants, a detailed map of the
binding energetics can be obtained, but the process can be very laborious because individual
mutant proteins must be made and analyzed separately. In particular, a comprehensive analysis
of an antigen binding site would ideally encompass all CDR residues, and this would require the
analysis of dozens or even hundreds of point mutants." (see page 416, right column, first
paragraph). Vajdos solution to this dilemma was to make use of a shotgun scanning mutagenesis
which "uses phage displayed libraries of protein mutants constructed using degenerate codons
with restricted diversity." While this method of making libraries of mutants representative of the
potential antigen binding CDR residues was an improvement over previous strategies as taught
by Vajdos, it nonetheless required extensive experimentation to comprehensively scan the
potential CDR sequence space (see page 416, right column, 2nd paragraph and pages 425-427,
Materials and Methods.)
Furthermore, even after performing this comprehensive scanning mutagenesis of all CDR
residues from the particular anti-ErB2 antibody under study, Vajdos would still not have been
able to say which CDR residues were actually involved in antigen binding, and which were
involved in stabilizing the secondary and tertiary structure of the CDRs within the context of the
heavy and light chains as a whole, without the structure of the unbound antigen-binding site of
the antibody to aid in their analysis (see, in particular, Discussion, pages 422-425).
Rather, Vajdos needed to perform not only a comprehensive shotgun scanning mutagenesis of all
CDR residues of the antibody under study, but also needed a structure of the unbound antigen binding site in hand to gain a sufficient understanding of the contribution of each CDR to
antigen-binding to adequately predict which CDR residues can be changed, and to what extent,
or in what context of additional compensatory mutations in other regions of the antibody.
Moreover, given an amino acid substitution that ablated binding, without the crystal structure in
hand, still further experimentation would have been required to determine the flexibility in this
particular residue, i.e., it's general tolerance or intolerance to change.
As yet another example to illustrate the sensitivity of some antibodies to changes in their CDR residues, especially CDR3, consider the teachings of Bedouelle et al. (FEBS J. 2006 Jan;273(1):34-46, cited herewith). While Bedouelle did not comprehensively scan all the CDR residues of their antibody using a combination of alanine and homologous substitutions as shown in Vajdos, Bedouelle did examine the effects of alanine substitutions on each of the residues of the antibody heavy and light chain CDR3 regions and showed mutation of certain residues cause a >100 fold drop in binding affinity (see Table 1). As described by Bedouelle, some of these loss of function mutations were hypothesized to have a direct effect on antigen binding while others were hypothesized to indirectly affect the conformation of the antigen binding site, thereby indirectly affecting antigen binding (see Discussion Section). Thus, the teachings of Bedouelle provide further illustration of the unpredictability of making mutations within the CDR region of an antibody.
Notably, while the teachings of Vajdos and Bedouelle demonstrate the unpredictable effects of even single amino acid changes on antibody:antigen binding, there is an additional level of unpredictability in the art associated with making multiple changes in any given CDR(s).
In particular, even in those instances where one can show certain residues of a given CDR are generally tolerant of single amino acid changes, this does not necessarily mean a combination of single amino acid changes, even to the same residues shown to tolerate change when mutated in isolation, will be tolerated. As an example consider Brown et al. (J Immunol. 1996 May 1;156(9):3285-91, cited herewith) which describes how the Vh CDR2 in a particular antibody was generally tolerant of single amino acid changes; however, the antibody lost binding upon the introduction of pairs of single amino changes in the same region (see, in particular Tables I and II and column bridging paragraph on page 3290).
Additionally, as emphasized by the teachings of Colman (Research in Immunology, 145:33-36, 1994, cited herewith) the type of CDR amino acid substitution, i.e., conservative vs. non-conservative, is not necessarily a good predictor of antigen binding: "[t]he above examples paint a confusing picture of the specificity of antibody-antigen interaction. In one structural context, a very conservative substitution may abolish binding; in another, a nonconservative substitution may have very little effect on the binding affinity.” (see pg. 35, top of left column). Rudikoff et al. (Proc. Natl. Acad. Sci. USA, 79: 1979-1983, March 1982, cited herewith) provides another example of how even a conservative change to a single amino acid residue in a CDR region of an antibody can ablate antigen binding (see, for example, Abstract).
Given the above the skilled artisan the teachings of the instant specification and/or the knowledge in the prior art were insufficient to establish possession of the breadth of variants encompassed by the instant claims which will preserve PD-L1 / PD-1-binding to the extent necessary to, e.g., block the interaction of these proteins with their cognate receptor / ligand to the extent necessary to preserve relief of checkpoint inhibition.
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 PD-L1 and PD-1-binding antibodies 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 antibodies.
No claims are allowed. However, claims 33, 34 and 36 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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