DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-9, 14, 16-28 are pending and are being acted upon.
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 2, 4 and 8-9 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 2 is indefinite in the recitation that the “CDRs” comprise the sequences set forth in “SEQ ID NO: 1 or SEQ ID NO: 42, SEQ ID NO: 2 or SEQ ID NO: 43, SEQ ID NO: 3 or SEQ ID NO: 44, SEQ ID NO: 4 or SEQ ID NO: 45, SEQ ID NO: 5 or SEQ ID NO: 46 and SEQ ID NO: 6”. It is not clear what sequences are required. For example, could one select two “CDRs” from the list? Does the claim require CDRs from SEQ ID NO: 1, i.e. is it indicating that SEQ ID NO: 1 represents more than 1 CDR? The scope of the claims is unclear and indefinite.
Claims 4 and 9 are indefinite in the recitation of a trimeric polypeptide complex comprising a 4-1BB scFV or EGFR VHH comprising SEQ ID NO: 19, or SEQ ID NO: 28, respectively. Said SEQ ID Nos: are nucleic acid sequences, and it is unclear how a trimeric polypeptide can comprise an 4-1BB scFV or EGFR VHH comprising a nucleic acid sequence. For example, does the claim encompass a polypeptide complex further comprising a nucleic acid, or are the claims meant to be directed to a scFV and VHH encoded by the nucleotide sequences. For the purposes of applying prior art, the claims are being interpreted as a 4-1BB scFV encoded by SEQ ID NO: 19, or a EGFR VHH encoded by SEQ ID NO: 28.
Claims 8-9 are indefinite in the recitation of a single-domain antibody (VHH). A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 8-9 recites the broad recitation of a single domain antibody, and the claim also recites VHH, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 14, 16-17 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1, from which the claims depend, requires a trimeric polypeptide with three monomers, while claims 14, 16017 encompass a single monomer. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-9, 14, 16-28 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. Specifically, there is insufficient written description to demonstrate that applicant was in possession of the claimed genus of “functional equivalent variants” of a homotrimerization domain or “functional equivalents” of CDRs.
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 MPEP 2163.
The present claims are directed to a trimeric polypeptide comprising a homotrimerization domain selected from the group consisting of the collagen XVIII homotrimerization domain, the collagen XV homotrimerization domain and “a functionally equivalent variant thereof.” This would encompass polypeptides with numerous amino acid substitutions, deletions, or additions, that function in homotrimerization. Thus, the claims encompass a large genus of structurally different homotrimerization domains with distinct amino acid sequences. The state of the art is such that protein chemistry is one of the most unpredictable areas of biotechnology. Whisstock et al (Quarterly Review of Biophysics, 2003, 36, pp307-340) teach that the prediction of protein function from sequence and structure is a difficult problem, because homologous proteins often have different functions. Even single amino acid changes in a proteins amino acid sequence can have dramatic effects on protein function. For example, Wang et al., 2001, show that a single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipids growth factor receptors (e.g., abstract). These references demonstrate that even a single amino acid substitution or what appears to be an inconsequential chemical modification will often dramatically affect the biological activity and characteristic of a protein. The instant specification does not disclose any species of “functional equivalent”, nor does the specification disclose a correlation between structure and homotrimerization function.
Claim 2 also encompass certain CDRs, or “functional equivalents” thereof. This would encompass a genus of different CDRs with numerous amino acid substitutions, deletions, or additions. Furthermore, the claim potentially encompasses selecting only two CDRs from the list and does not necessarily require 6 CDRs. The state of the art is such that the 6 CDRs of an antibody are critically involved in antigen binding, that even single amino acid changes can alter antigen specificity of binding, and that CDR mutations are unpredictable in terms of affinity, specificity, and solubility, and are also context dependent (see Hall, 1992, and Rabia, 2018). The specification discloses a VH CDR1 of SEQ ID NO: 1 or 42, a VH CDR2 of SEQ ID NO: 2 or 43, a VH CDR3 of SEQ ID NO: 3 or 44, a VL CDR1 of SEQ ID NO: 4 or 45, a VL CDR2 of SEQ ID NO: 5 or 46, and a VL CDR3 of SEQ ID NO: 6. This is not sufficiently representative of the genus of CDRs encompassed by the present claims. For example, the present claims encompass CDR variants with any number of mutations, but none are disclosed. Furthermore, claim 2 also encompasses mixing the CDRs, i.e. SEQ ID NO: 1 could be VL CDR1 or VH CDR3, or varying the CDRs such that they could be mixed and matched, and the specification does not disclose any scFV having mixed and matched CDRs.
The instant application has not provided a sufficient description showing possession of the necessary 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 of peptides. Further, the Court has interpreted 35 U.S.C. §112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe Inc, 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 43 USPQ2d 1398 (Fed Cir. 1997)).
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.)
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Amendment to claims 1 and 2 to remove the “functionally equivalent” limitation, and further amendment to claim 2 to recite that the anti-4-1BB specific scFV comprises a VH CDR1 of SEQ ID NO: 1 or 42, a VH CDR2 of SEQ ID NO: 2 or 43, a VH CDR3 of SEQ ID NO: 3 or 44, a VL CDR1 of SEQ ID NO: 4 or 45, a VL CDR2 of SEQ ID NO: 5 or 46, and a VL CDR3 of SEQ ID NO: 6, would be remedial.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3, 5-8, 14, 16-17, 24-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2019234187, in view of Huston, 1993 and Alvarez-Cienfuegos, 2016 (of record).
WO2019234187 teaches a trimeric polypeptide complex comprising three monomer polypeptides wherein each monomer polypeptide comprises: a) an anti-4-1BB specific agonistic single-chain antibody fragment (scFv) b) a homotrimerization domain selected from the group consisting of the collagen XVIII homotrimerization domain (TIEXVIII), and c) a polypeptide region which is capable of specifically binding to EGRF tumor associated antigen, wherein said polypeptide region is a VHH (see pages 1-4 and 66-68, in particular). WO2019234187 teaches that the EGFR VHH is positioned C-terminal to the homotrimerication domain (See drawings). WO2019234187 teaches a polynucleotide encoding said polypeptide and a vector and host cell comprising said polynucleotide (See pages 36-40, in particular). WO2019234187 teaches a pharmaceutical composition comprising said trimeric polypeptide, and a method of treating cancer comprising administering to as subject in need thereof said trimeric polypeptide, including breast cancer, colorectal cancer, small-cell lung cancer, or EGFR+ cancers (see pages 43-47, in particular). WO2019234187 teaches using humanized antibodies and antibody fragments and that doing so reduces immunogenicity in human individuals and improves safety (See pages 24-27, in particular).
The reference differs from the claimed invention in that it does not explicitly teach that the 4-1BB scFV has the VH domain N-terminal to the VL domain.
Huston teaches that scFv can be designed by linking a VH and VL via Gly4-Ser linker, and that either orientation can be used , i.e. VH-linker-VL (VH domain N-terminal to the VL domain) or VL-linker-VH (see abstract, in particular). Huston teach the linkers can be Gly4Ser repeats of 15 amino acids in length, i.e. three repeats of said Gly4Ser linker (see Table 1, in particular). See also Alvarez-Cienfuegos, which teaches scFV orientated with VH domain N-terminal to VL domain, wherein they can be trimerized with a TIE homotrimerization domain (See Fig. 1, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, to orient the scFV of the trimeric polypeptide of WO2019234187, using a VH-linker-VL orientation, as taught by Huston and Alvarez-Cienfuegos. Selecting from the two possible scFV orientations would involve choosing among a finite number of predictable options which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385).
Claim 2-4, 18-23 are rejected under 35 U.S.C. 103(a) as being unpatentable over WO2019234187, Huston, 1993 and Alvarez-Cienfuegos, 2016, as applied to claims 1, above, and further in view of US 2018/0327504 and Chester, 2016.
The combined teachings of WO2019234187, Huston, and Alvarez-Cienfuegos are discussed above.
They do not explicit teach a 4-1BB scFV with CDRs of claim 2, or combination with a checkpoint blocker.
The ‘504 publication teaches a 4-1BB specific humanized antibody agonist SAP3.28 with mFR2 being substituted back to murine that is potent and useful in therapeutic applications for treating cancer ((See page 1, Fig. 9). The ‘504 publication teaches that said SAP3.28 has VH CDR1-3 of SEQ ID NO: 13-15, which comprise a sequence identical to SEQ ID Nos: 42, 2, and 44, respectively, of the instant claims. The ‘504 publication teaches that the SAP3.28 has VL CDR1-4 of SEQ ID NO: 16-18, which comprise a sequence identical to SEQ ID Nos: 45, 46, and 6, of the instant claims, respectively (see Table 2, page 14, in particular). The ‘504 publication teaches that the antibodies can be in the form of an scFV and are useful in bispecific format or as a conjugate with another antibody (see page 4, in particular). The ‘504 publication teaches that the 4-1BB stimulating antibodies can be used in combination treatment with a PD-1 or PD-L1 checkpoint inhibitor antibodies (see pages 10-11, in particular).
Chester teaches that 4-1BB agonists and checkpoint blockade may represent an optimal combination that has the potential to activate anti-tumor immune effectors by complementary mechanisms, simultaneously removing the brakes and stepping on the accelerator. Chester teaches atezolizumab and pembrolizumab are promising checkpoint inhibitor antibodies.
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was made to apply the teachings of the ‘504 publication by using the humanized VH an VL of SAP3.28 as the VH and VL in the 4-1BB scFV in the trimer polypeptide complex made obvious by WO2019234187, Huston, and Alvarez-Cienfuegos. One of ordinary skill in the art at the time the invention was made would have been motivated to do so, and have a reasonable expectation of success, because the ‘504 publication teaches that the human SAP3.28 antibody is a potent 4-1BB agonist that has therapeutic application in treating cancer. Regarding claim 3, it is noted that it would be obvious to construct the scFV using the VH and VL domains of said humanized SAP3.28 with a 15 amino acid Gly4Ser linker, since this is a known linker that can be used in scFv construction by linking a given VH and VL (see Huston and Alvarez-Cienfuegos). SEQ ID NO: 19 of the present claims encodes an scFv with the VH and VL of said humanized SAP3.28 linked via a 15 amino acid Gly4Ser linker (see the instant specification page 51, said SEQ ID NO: 19 encodes a VH domain and VL domain from humanized clone SAP3.28 with preserved murine FR3). Therefore, being encoded by SEQ ID NO: 19 would be a latent or inherent property of scFV made obvious above.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the trimeric polypeptide complex made obvious by Huston and Alvarez-Cienfuegos, with a checkpoint inhibitor, such as atezolizumab or pembrolizumab, as taught by the ‘504 publication and Chester. The ordinary artisan would have been motivated to so with a reasonable expectation of success since the ‘504 publication teaches that combining 4-1BB agonist antibodies with checkpoint inhibitors can treat cancer and Chester teaches the advantages of doing so include the potential to activate anti-tumor immune effectors by complementary mechanism, simultaneously removing the brakes and stepping on the accelerator.
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.
Claim 1-8, 14, 16-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 12,454,577, in view of Huston, 1993, Alvarez-Cienfuegos, 2016 (of record), 2018/0327504 and Chester, 2016.
The ‘577 patent claims a trimeric polypeptide complex comprising three monomer polypeptides comprising a homotrimerization domain of collagen XVIII and an agonist scFV of a TNFR family costimulatory receptor, and further comprising a polypeptide which binds to a tumor associated antigen at the N or C terminus of the homotrimerization domain. The ‘577 patent claims that the tumor associated antigen is EGFR and the binding agent is an anti-EGFR nanobody (i.e. a VHH). The ‘577 patent claims that the TNFR family costimulatory receptor is 4-1BB and that the agonist is an scFV> The ‘577 patent claims a polynucleotide encoding said trimeric polypeptide, vectors and host cells comprising, and methods of treating cancer, such as colorectal cancer, comprising administering said polypeptide.
Although not specifically claimed in the ‘577 patent, constructing the scFV with VL-linker-VL orientation and using a SAP3.28 scFV, or combining with a checkpoint inhibitor would be obvious in view of Huston, Alvarez-Cienfuegos, the ‘504 publication, and Chester, for the same reasons set forth above.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.
Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644