DETAILED ACTION
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 .
Claim Status
The preliminary amendment filed 02/05/25 is acknowledged. Claims 1, 5, 8, 12, 15, 17, 21, 25, 27, 29-34, 36, 38, 40, and 43 are amended. Claims 2-4, 6, 7, 9-11, 13, 14, 16, 18-20, 22-24, 26, 44, and 45 are cancelled. Claims 1, 5, 8, 12, 15, 17, 21, 25 and 27-43 are pending and under examination.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code [see at least p. 19, par. 6; p. 20, par. 1 and 2]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112b
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.
Claim 1 and 27-43 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 1 recites an anti-ILT4 binding domain comprising a heavy chain variable region CDR set and a first light chain variable region CDR set, and an additional second light chain variable region CDR set. It is unclear whether the claim requires both light chain CDR sets to be present in the same binding domain or whether one of the recitations is intended to be an alternative. The specification discloses embodiments in which the second light chain CDRs are paired with the disclosed heavy chain CDRs, but does not provide any embodiments in which two light chains are in a single embodiment. Accordingly, the metes and bounds of the claim cannot be determined with reasonable certainty. To advance compact prosecution, the examiner interprets this embodiment as the heavy chain CDRs of SEQ ID NOs: 1, 3, and 5, and either the light chain CDRs of SEQ ID NOs: 10, 11, and 12 or SEQ ID NOs: 6, 7, and 8. Claims 27-43 are included in this rejection for explicitly or implicitly requiring the composition of claim 1 without correcting the indefiniteness. Appropriate correction is required.
Therefore, claims 1 and 27-43 are rejected under 35 U.S.C. 112(b) as being indefinite.
Claim Rejections - 35 USC § 112a
Written Description
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 1, 12, 15, and 27-43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), 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 MPEP 2163(II)(3)(a)(i)(C).
Claim 1 recites a bispecific construct comprising several CDRs “or conservative modifications thereof,” which encompasses a genus of proteins. The specification, however, only demonstrates a single bispecific construct (CDX-585) comprising a specific variable heavy and a specific variable light chain, as well as its corresponding binding data. As discussed above, the claims are not limited to those species, but include many possible substitutions and CDR combinations. Crucially, protein chemistry is unpredictable and the art recognizes that even a single amino acid substitution can abolish protein activity [see Rudikoff et al., abstract]. The specification fails to provide a representative number of species within the recited genus, adequate structure-function correlation, or other identifying characteristics of the genus as a whole, and accordingly, the disclosure does not reasonably convey possession of the full scope of possible amino acid modifications and subsequent CDR combinations.
Further, claim 1 recites consensus CDR sequences comprising alternative amino acid residues at one or more positions, which encompass multiple distinct CDR amino acid sequences. As discussed above, protein chemistry is unpredictable and the art recognizes that even a single amino acid substitution can abolish protein activity. The specification fails to provide a representative number of species within the recited genus, adequate structure-function correlation, or other identifying characteristics of the genus as a whole, and accordingly, the disclosure does not reasonably convey possession of the full scope of possible CDR combinations and amino acid modifications.
Further, claim 1 recites heavy and light chain variable region sequences and sequences “at least 95% similar thereto,” which encompasses a genus of proteins. The recited language includes modifications to CDRs, which are critical to protein binding. As discussed above, protein chemistry is unpredictable and the art recognizes that even a single amino acid substitution can abolish protein activity. As such, the specification fails to provide a representative number of species within the recited genus, adequate structure-function correlation, or other identifying characteristics of the genus as a whole, and accordingly, the disclosure does not reasonably convey possession of the full scope of possible CDR combinations and amino acid modifications. Claims 12, 15, and 27-43 are included in this rejection for explicitly or implicitly requiring this composition without correcting the lack of written description.
Therefore, claims 1, 12, 15, and 27-43 are rejected under 35 U.S.C. 112(a) for lack of written description.
Claims 1, 5, 8, 12, 15, 17, 21, and 27-43 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.
Independent claims 1, 8, 17, and 21 recite bispecific constructs comprising binding domains defined by various alternative CDRs or full variable heavy and light chains, which encompasses a genus of proteins. As discussed above, the specification only describes the exemplified bispecific construct CDX-585, which comprises the specific anti-ILT4 and PD-1 binding domains disclosed therein [see specification, table 3, SEQ ID NOs: 63 and 64]. As discussed above, protein chemistry is unpredictable and the art recognizes that even a single amino acid substitution can abolish protein activity. There is no evidence in the specification to support that the inventors had possession of all combinations of the claimed CDRs and chain embodiments.
Furthermore, absent amino acid modifications which were addressed above, it is noted that many of the possible embodiments encompassed in claims 1, 5, 8, 17, and 21 differ from the exemplified CDX-585 construct by requiring at least one alternative amino acid residue of a CDR compared to the CDRs disclosed in CDX-585. For example, an embodiment of claim 1 may be identified as the following:
anti-ILT4 binding domain comprising:
VH CDR SEQ ID NOs: 21, 3, and 22
VL CDR SEQ ID NOs: 23, 24, and 8
Anti-PD-1 binding domain comprising:
VH CDR SEQ ID NOs: 31, 36, and 41
VL CDR SEQ ID NOs: 69, 74, and 79
In this embodiment, SEQ ID NOs: 3 and 79 do not correspond to the disclosed sequence of CDX-585 as both differ by a single amino acid. Given the unpredictability of modifications as discussed above, the specification fails to provide a representative number of species within the recited genus, adequate structure-function correlation, or other identifying characteristics of the genus as a whole, and accordingly, the disclosure does not reasonably convey possession of the full scope of possible CDR and chain combinations. Claims 5, 12, 15, and 27-43 are included in this rejection as they explicitly or implicitly require the composition of claim 1 without correcting the lack of written description.
Therefore, claims 1, 5, 8, 12, 15, 17, 21, and 27-43 are rejected under 35 U.S.C. 112(a) for lack of written description.
Enablement
Claims 32, 33, and 34, and 40-43 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 embodiments comprising CDRS disclosed in CDX-585, such as the embodiment of SEQ ID NOs: 19, 20, 59, and 60, it does not reasonably provide enablement for all possible amino acid alternatives as disclosed in claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As discussed above, a single modification to a CDR may abolish binding activity, and thus, without sufficient guidance, representative examples, or an identified structure function relationship, a skilled artisan would be required to generate and test every individual antibody variant to determine which of the numerous constructs encompassed by claim 1 will retain the binding, signaling, and functional properties necessary to produce the desired outcomes. This constitutes undue experimentation. Claims 40-43 are included in this rejection because they explicitly or implicitly require the method of claim 33.
Therefore, claim 32, 33, and 34, and 40-43 are rejected under 35 U.S.C. 112(a) for lack of enablement.
Claims 34 and 35 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 cancer, does not reasonably provide enablement for all conditions and diseases. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 34 broadly recites treatment of “a condition or disease” and claim 35 limits the method to conditions or diseases in which stimulation of an immune response is desired. Conditions and diseases are characterized by numerous different causes, so it is unclear how administration of this particular bispecific construct would be effective in all such cases. Furthermore, while the specification demonstrates that CDX-585 can effectively treat melanoma, and therefore supports the general concept of treating cancer, the specification provides no guidance sufficient to determine which other conditions or diseases could be treated within the full scope of the claim, without undue burden, even when the conditions and diseases are limited to those in which stimulation of an immune response is desired.
Therefore, claims 34 and 35 are rejected under 35 U.S.C. 112(a) for lack of enablement.
Subject Matter Free of the Art
The examiner notes that the specific bispecific construct comprising the anti-ILT4 variable region sequences of SEQ ID NOs: 19 and 20 and the anti-PD-1 variable region sequences of SEQ ID NOs: 59 and 60 is supported by the original disclosure. Accordingly, claims limited to that specific embodiment would not be subject to the present written description. Furthermore, the prior art of record does not teach or suggest that that specific construct. Claims appropriately limited to that disclosed embodiment, and otherwise in compliance with all other statutory requirements, may place the claims in condition for allowance.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Tirone D Johnson whose telephone number is (571)272-1256. The examiner can normally be reached M-F, 9-5 ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571)272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TIRONE D. JOHNSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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