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 .
Election/Restrictions
Applicant’s election without traverse of Method(A); colorectal cancer as the cancer species; the first and second TTA are the same; and SEQ ID NO: 145 as the polypeptide species in the reply filed on 07/06/2026 is acknowledged.
Claims 2, 6, 7, 10, 11, 14, 27, 49, 50, 59, 71, and 72 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/06/2026.
Claims 1, 3, 18, 32, 36, 38-43, and 58 are examined on the merits in the present Office Action.
Claim Rejections - 35 USC § 112
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 40 is 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 40 recites the limitation "half-life extension domain" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 102
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.
Claims 1, 36, 38, 39, 40, 41, 42, and 43 are rejected under 35 U.S.C. 102(a)(1) and 35 USC 102(a)(2) as being anticipated by May et al (WO2019051102A2), hereinafter May.
May discloses COnditional Bispecific Redirected Activation constructs, or COBRAs, administered in an active pro-drug format for the treatment of cancer, wherein the pro-drug format is “Format 2” comprising from the N-to-C-terminus:
a) a first single domain antigen binding domain (sdABD) that binds to a human tumor target antigen (TTA) (sdABD-TTA);
b) a first domain linker;
c) a constrained Fv domain comprising:
i) a first variable heavy domain comprising a vhCDRl, vhCDR2 and vhCDR3;
ii) a constrained non-cleavable linker (CNCL); and
iii) a first variable light domain comprising vlCDRl, vlCDR2 and vlCDR3;
d) a second domain linker;
e) a second sdABD-TTA;
f) a cleavable linker (CL);
g) a constrained pseudo Fv domain comprising:
i) a first pseudo light variable domain;
ii) a non-cleavable linker (NCL); and
iii) a first pseudo heavy variable domain;
h) a third domain linker; and
i) a third sdABD that binds to human serum albumin;
wherein said first variable heavy domain and said first variable light domain are capable of binding human CD3 but said constrained Fv domain does not bind CD3. Upon exposure to tumor proteases, the constructs are cleaved and activated, such that they can bind both tumor target antigens (TTAs) as well as CD3, thus recruiting T cells expressing CD3 to the tumor, resulting in treatment (Abstract, Para. 0005, and Claim 1). In some embodiments, the first and second TTA are the same (Para. 0011), wherein the first and second TTA is selected from EGFR, EpCAM, FOLR1 and B7H3 (Para. 0013). The sdABD-TTAs have the amino acid sequence selected from the group consisting of SEQ ID NO: l (alpha-EGFR1); SEQ ID NO:5 (alpha-EGFR2); SEQ ID NO:9 (h-alpha-EGFR1); SEQ ID NO:13 (h-alpha-EGFR2); SEQ ID NO:17 (alpha-FOLR1 h77-2), SEQ ID NO:21 (alpha-FORL1 h59.3); SEQ ID NO:25 (alpha-FORL1 h22-4); SEQ ID NO:29 (alpha-B7H3 hF7); SEQ ID NO:33 (alpha-B7H3 hF12); SEQ ID NO:37 (alpha-EpCAM h13); and SEQ ID NO:41 (alpha-EpCAM h23) (Para. 0013), each 100% identical to corresponding SEQ ID numbers in the instant claims. The half-life extension domain has an amino acid sequence of SEQ ID NO: 45 (Para. 0014), which is identical in sequence to SEQ ID NO: 45 of the instant claims. The cleavable linker is cleaved by a human protease selected from the group consisting of MMP2, MMP9, Meprin A, Meprin B, Cathepsin S, Cathepsin K, Cathespin L, GranzymeB, uPA, Kallekriein7, matriptase and thrombin (Para. 0015). The pro-drug can be the Format 2 construct Pro186 having the amino acid sequence of SEQ ID NO: 145 (Para. 0016, Claim 13, and Figure 62B), which is identical in sequence to Pro186 (SEQ ID NO: 145) of the instant claims. Pro186 is an anti-EGFR COBRA having an MMP9 cleavable linker (Para. 0055-0056, Para. 0059, and Figure 37). In Pro186, an active VH and an active VL are separated by 8-mer constrained noncleavable linker that does not allow the VH and VL to self-assemble into an active antigen binding domain (Para. 00192). Pro186 (elected species) fully comprises the sdABD of SEQ ID NO: 5 (alpha-EGFR2) (see Sequence Alignments below). Lastly disclosed is a method of treating cancer in a subject comprising administering the pro-drug (Para. 0005, 00276, and Claim 18).
Thus, May meets the limitations of instant claims 1, 36, 38, 39, 40, 41, 42, and 43.
Half-life Extension Domain: SEQ ID NO: 45 (instant claims) vs SEQ ID NO: 45 (prior art). (Note: Sequence Alignment based on application 16/124/556 from the same patent family as WO2019051102A2).
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The sdABD of SEQ ID NO: 5 (alpha-EGFR2) is fully comprised in Pro186 (elected species) at positions 1-124. Pro186 (SEQ ID NO: 145) (Note: Sequence Alignment based on application 16/124/556 from the same patent family as WO2019051102A2).
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Pro186: SEQ ID NO: 145 (instant claims) vs SEQ ID NO: 145 (prior art) (Note: Sequence Alignment is based on (Note: Sequence Alignment based on application 16/124/556 from the same patent family as WO2019051102A2).
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Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 3, 18, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over May, as applied to claims 1, 36, 38, 39, 40, 41, 42, and 43 above, and further in view of Spano et al (Spano, J-P., et al. Annals of oncology 16.1 (2005): 102-108), hereinafter Spano.
The teachings of May have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the type of cancer treated is colorectal cancer, a type of solid tumor.
However, Spano teaches that epidermal growth factor receptor (EGFR) is overexpressed in many types of cancers, including colorectal cancer, and reflects more aggressive histological and clinical behaviors. In particular, EGFR overexpression in colorectal patients is significantly associated with tumor-node-metastasis stage T3 (Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of treating cancer in a subject comprising administering the COBRA construct Pro186 disclosed by May such that the cancer is a colorectal cancer. One of ordinary skill in the art would have been motivated to do so since colorectal cancer can be characterized by overexpression of EGFR as taught by Spano; and the COBRA polypeptides disclosed by May can be used to treat EGFR- expressing tumors. Therefore, one of ordinary skill in the art would reasonably expect that a patient having EGFR-expressing colorectal cancer can be effectively treated using the COBRA polypeptides targeting EGFR.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over May, as applied to claims 1, 36, 38, 39, 40, 41, 42, and 43 above, and further in view of Eisenhauer et al (Eisenhauer, E A et al. European journal of cancer (Oxford, England : 1990) vol. 45,2 (2009): 228-47. doi:10.1016/j.ejca.2008.10.026), hereinafter Eisenhauer.
The teachings of May have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the patient has an ECOG performance status of at least grade 1 and/or a measurable disease as per RECIST v1.1 criteria and documented by CT and/or MRI.
However, Eisenhauer teaches that RECIST 1.1 is a standard way to measure the response of a tumor to treatment (Abstract and Background). To assess objective response, it is necessary to estimate the overall tumor burden at baseline and use this as a comparator for subsequent measurements. Only patients with measurable disease at baseline are included in protocols where objective tumor response is the primary endpoint, wherein measurable disease is defined by the presence of at least one measurable lesion (Section 3.1.1 and Section 4.1) and can be determined using, for example, CT or MRI (Section 1.4 and Section 3.1.1).
It would have been obvious to one of ordinary skill in the art to modify the method of treating cancer taught by May such that the patient administered a COBRA such as Pro186 is one that has a measurable tumor as determined by RECIST 1.1 criteria and documented via CT or MRI assessments. One of ordinary skill in the art would have been motivated to do so because to determine the objective response of a tumor to treatment the patient should have measurable disease at baseline as taught by Eisenhauer. Therefore, one of ordinary skill in the art would reasonably expect that patients having a measurable tumor per RECIST v1.1 criteria represent a population in need of therapeutic intervention (e.g. with the COBRA polypeptide Pro186), while also severing as a cohort for assessing objective treatment response.
Double Patenting
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.
Claims 1, 3, 18, 36, 38-43, and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11406710B2 in view of May et al (WO2019051102A2), hereinafter May and Spano et al (Spano, J-P., et al. Annals of oncology 16.1 (2005): 102-108), hereinafter Spano.
The issued claims recite a polypeptide comprising, from N- to C-terminal:
a) a first single domain antigen binding domain (sdABD) that binds to a human tumor target antigen (TTA) (sdABD-TTA);
b) a first domain linker;
c) a constrained Fv domain comprising:
i) a first variable heavy domain comprising a vhCDR1, vhCDR2 and vhCDR3;
ii) a constrained non-cleavable linker (CNCL); and
iii) a first variable light domain comprising vlCDR1, vlCDR2 and vlCDR3,
wherein the CNCL is positioned between the first variable heavy domain and the first variable light domain and prevents the first variable heavy domain and the first variable light domain from interacting to form an active Fv capable of binding CD3;
d) a second domain linker;
e) a second sdABD-TTA;
f) a cleavable linker (CL);
g) a pseudo Fv domain comprising:
i) a first pseudo variable light domain;
ii) a non-cleavable linker (NCL); and
iii) a first pseudo variable heavy domain;
h) a third domain linker; and
i) a third sdABD that binds to human serum albumin;
wherein:
said first variable heavy domain and said first variable light domain are capable of binding human CD3 but said constrained Fv domain does not bind CD3; and the polypeptide does not bind CD3 when the CL is intact (issued claim 1). In some embodiments, said first and second TTA is the same (issued claim 7) and selected from EGFR, EpCAM, FOLR1 and B7H3 (issued claim 9). The cleavable linker is cleaved by a human protease selected from the group consisting of MMP2, MMP9, Meprin A, Meprin B, Cathepsin S, Cathepsin K, Cathespin L, GranzymeB, uPA, Kallekriein7, matriptase and thrombin (issued claim 10).
The issued claims do not recite a method of treating cancer in a subject comprising administering the polypeptide (i.e. COBRA), wherein the polypeptide is Pro186 and the cancer is colorectal cancer.
However, May teaches a method of treating cancer in a subject comprising administering the pro-drug (Para. 0005, 00276, and Claim 18), wherein the prodrug the Format 2 construct Pro186 having the amino acid sequence of SEQ ID NO: 145 (Para. 0016, Claim 13, and Figure 62B), which is identical in sequence to Pro186 (SEQ ID NO: 145) of the instant claims. Pro186 is an anti-EGFR COBRA having an MMP9 cleavable linker (Para. 0055-0056, Para. 0059, and Figure 37). Pro186 fully comprises the sdABD of SEQ ID NO: 5 (alpha-EGFR2). “Format 2” constructs have the structure set forth in issued claim 1 (and instant claim 1) (see Summary of the Invention, issued specification).
Spano further teaches that epidermal growth factor receptor (EGFR) is overexpressed in many types of cancers, including colorectal cancer, and reflects more aggressive histological and clinical behaviors. In particular, EGFR overexpression in colorectal patients is significantly associated with tumor-node-metastasis stage T3 (Abstract).
It would have been obvious to one of ordinary skill in the art to administer the COBRA construct of the issued claims to a patient having cancer, wherein the COBRA construct is substituted with Pro186 and the cancer is a colorectal cancer. One of ordinary skill in the art would have been motivated to do so since “Format 2” COBRA constructs such as Pro186 can be used to effectively treat cancer in a subject. Further, it would have been obvious to artisans to substitute the EGFR-specific COBRA recited in the issued claims with the EGFR-specific COBRA Pro186 disclosed by May and having the same general structure (“Format 2”) since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Lastly, colorectal cancer can be characterized by overexpression of EGFR as taught by Spano. As such, the EGFR-specific COBRA Pro186 can be used to effectively treat EGFR-expressing tumors. Therefore, one of ordinary skill in the art would reasonably expect that the COBRA construct of the issued claims can be used to effectively treat colorectal cancer in a subject, wherein the COBRA construct is the EGFR-specific COBRA Pro186.
Claim 32 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11406710B2 in view of May and Spano, as applied to claims 1, 3, 18, 36, 38-43, and 58 above, and further in view of Eisenhauer et al (Eisenhauer, E A et al. European journal of cancer (Oxford, England : 1990) vol. 45,2 (2009): 228-47. doi:10.1016/j.ejca.2008.10.026), hereinafter Eisenhauer.
The teachings of the issued claims in view of May and Spano have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the patient has an ECOG performance status of at least grade 1 and/or a measurable disease as per RECIST v1.1 criteria and documented by CT and/or MRI.
However, Eisenhauer teaches that RECIST 1.1 is a standard way to measure the response of a tumor to treatment (Abstract and Background). To assess objective response, it is necessary to estimate the overall tumor burden at baseline and use this as a comparator for subsequent measurements. Only patients with measurable disease at baseline are included in protocols where objective tumor response is the primary endpoint, wherein measurable disease is defined by the presence of at least one measurable lesion (Section 3.1.1 and Section 4.1) and can be determined using, for example, CT or MRI (Section 1.4 and Section 3.1.1).
It would have been obvious to one of ordinary skill in the art to modify the method of treating colorectal cancer taught by the issued claims in view of May and Spano such that the patient administered a COBRA such as Pro186 is one that has a measurable tumor as determined by RECIST 1.1 criteria and documented via CT or MRI assessments. One of ordinary skill in the art would have been motivated to do so because to determine the objective response of a tumor to treatment the patient should have measurable disease at baseline as taught by Eisenhauer. Therefore, one of ordinary skill in the art would reasonably expect that patients having a measurable tumor per RECIST v1.1 criteria represent a population in need of therapeutic intervention (e.g. with the COBRA polypeptide Pro186), while also severing as a cohort for assessing objective treatment response.
Claims 1, 36, 38, 39, 40 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11744893B2 in view of Zhang et al (Zhang, Ting et al. World journal of gastroenterology vol. 21,6 (2015): 1804-13. doi:10.3748/wjg.v21.i6.1804), hereinafter Zhang.
The issued claim recites a method of treating cancer comprising administering a therapeutically effective amount of a polypeptide comprising the amino acid sequence of SEQ ID NO:147 (Pro225) to a patient in need thereof. As evidenced by instant claim 50 (currently withdrawn), Pro225 possesses the format outlined in instant claim 1. Pro225 targets B7H3 and comprises an MMP9 cleavable linker and the anti-HSA domain of the instant claims (SEQ ID NO: 45) (see Brief Description of the Drawings, Figure 45, and Figure 62C of the issued specification). Additionally, Pro225 comprises the B7H3 sdABD hF7 (SEQ ID NO: 29) (see Figures 5B and 62C), corresponding to SEQ ID NO: 29 (alpha B7H3-hF7) of the instant claims.
The issued claim does not recite that the cancer is colorectal cancer.
However, Zhang teaches that B7-H3 is highly expressed in many types of solid tumors and the expression of B7-H3 has been positively correlated with poor prognosis in colorectal cancer as well as with invasion and metastasis (Abstract, Core Tip, and Introduction).
It would have been obvious to one of ordinary skill in the art to modify the method of treating cancer in a subject comprising administering the polypeptide Pro225 such that the cancer is a colorectal cancer. One of ordinary skill in the art would have been motivated to do so since colorectal cancer can be characterized by overexpression of B7H3 as taught by Zhang; and the COBRA polypeptide Pro225 of the issued claims targets B7H3 and thus can be used to treat B7H3- expressing tumors. Therefore, one of ordinary skill in the art would reasonably expect that a patient having B7H3-expressing colorectal cancer can be effectively treated using the COBRA polypeptide Pro225 of the issued claims.
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Claim 32 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11744893B2 in view of Zhang, as applied to claims 1, 36, 38, 39, 40 and 41 above, and further in view of Eisenhauer et al (Eisenhauer, E A et al. European journal of cancer (Oxford, England : 1990) vol. 45,2 (2009): 228-47. doi:10.1016/j.ejca.2008.10.026), hereinafter Eisenhauer.
The teachings of the issued claims in view of Zhang have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the patient has an ECOG performance status of at least grade 1 and/or a measurable disease as per RECIST v1.1 criteria and documented by CT and/or MRI.
However, Eisenhauer teaches that RECIST 1.1 is a standard way to measure the response of a tumor to treatment (Abstract and Background). To assess objective response, it is necessary to estimate the overall tumor burden at baseline and use this as a comparator for subsequent measurements. Only patients with measurable disease at baseline are included in protocols where objective tumor response is the primary endpoint, wherein measurable disease is defined by the presence of at least one measurable lesion (Section 3.1.1 and Section 4.1) and can be determined using, for example, CT or MRI (Section 1.4 and Section 3.1.1).
It would have been obvious to one of ordinary skill in the art to modify the method of treating colorectal cancer taught by the issued claims in view of Zhang such that the patient administered a COBRA such as Pro225 is one that has a measurable tumor as determined by RECIST 1.1 criteria and documented via CT or MRI assessments. One of ordinary skill in the art would have been motivated to do so because to determine the objective response of a tumor to treatment the patient should have measurable disease at baseline as taught by Eisenhauer. Therefore, one of ordinary skill in the art would reasonably expect that patients having a measurable tumor per RECIST v1.1 criteria represent a population in need of therapeutic intervention (e.g. with the COBRA polypeptide Pro225), while also severing as a cohort for assessing objective treatment response.
Claims 1, 3, 18, 36, 38-43, and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11744892B2 in view of Spano et al (Spano, J-P., et al. Annals of oncology 16.1 (2005): 102-108), hereinafter Spano.
The issued claim recites a method of treating cancer comprising administering a therapeutically effective amount of a polypeptide comprising the amino acid sequence of SEQ ID NO:145 (Pro186) (corresponding to SEQ ID NO: 145 of the instant claims). Pro186 is an anti-EGFR “Format 2” COBRA construct having an MMP9 cleavable linker (see Figure 376 of issued patent). Further, Pro186 fully comprises the sdABD of SEQ ID NO: 5 (alpha-EGFR2), corresponding to SEQ ID NO: 5 of the instant claims. “Format 2” constructs have the structure set forth in issued claim 1 (and instant claim 1) (see Summary of the Invention, issued specification).
The issued claims does not recite that the cancer is colorectal cancer.
However, Spano teaches that epidermal growth factor receptor (EGFR) is overexpressed in many types of cancers, including colorectal cancer, and reflects more aggressive histological and clinical behaviors. In particular, EGFR overexpression in colorectal patients is significantly associated with tumor-node-metastasis stage T3 (Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of treating cancer recited by the issued claim such that the cancer is a colorectal cancer. One of ordinary skill in the art would have been motivated to do so since colorectal cancer can be characterized by overexpression of EGFR as taught by Spano; and the COBRA construct disclosed by the issued claim can be used to treat EGFR- expressing tumors. Therefore, one of ordinary skill in the art would reasonably expect that the COBRA construct Pro186 of the issued claims can be used to effectively treat a subject having colorectal cancer characterized by EGFR-overexpression.
Thus, the issued claims in view of Spano meet the limitations of instant claims 1, 3, 18, 36, 38-43, and 58.
Claim 32 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11744892B2 in view of Spano, as applied to claims 1, 3, 18, 36, 38-43, and 58 above, and further in view of Eisenhauer et al (Eisenhauer, E A et al. European journal of cancer (Oxford, England : 1990) vol. 45,2 (2009): 228-47. doi:10.1016/j.ejca.2008.10.026), hereinafter Eisenhauer.
The teachings of the issued claims in view of Spano have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the patient has an ECOG performance status of at least grade 1 and/or a measurable disease as per RECIST v1.1 criteria and documented by CT and/or MRI.
However, Eisenhauer teaches that RECIST 1.1 is a standard way to measure the response of a tumor to treatment (Abstract and Background). To assess objective response, it is necessary to estimate the overall tumor burden at baseline and use this as a comparator for subsequent measurements. Only patients with measurable disease at baseline are included in protocols where objective tumor response is the primary endpoint, wherein measurable disease is defined by the presence of at least one measurable lesion (Section 3.1.1 and Section 4.1) and can be determined using, for example, CT or MRI (Section 1.4 and Section 3.1.1).
It would have been obvious to one of ordinary skill in the art to modify the method of treating colorectal cancer taught by the issued claims in view of Spano such that the patient administered a COBRA such as Pro186 is one that has a measurable tumor as determined by RECIST 1.1 criteria and documented via CT or MRI assessments. One of ordinary skill in the art would have been motivated to do so because to determine the objective response of a tumor to treatment the patient should have measurable disease at baseline as taught by Eisenhauer. Therefore, one of ordinary skill in the art would reasonably expect that patients having a measurable tumor per RECIST v1.1 criteria represent a population in need of therapeutic intervention (e.g. with the COBRA polypeptide Pro186), while also severing as a cohort for assessing objective treatment response.
Claims 1, 3, 18, 36, 38-43, and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12478673B2 in view of May et al (WO2019051102A2), hereinafter May and Spano et al (Spano, J-P., et al. Annals of oncology 16.1 (2005): 102-108), hereinafter Spano.
The issued claims recite a method of treating cancer comprising administering a therapeutically effective amount of a protein to a patient in need thereof, the polypeptide comprising from N- to C-terminal:
a) a first single domain antigen binding domain (sdABD) that binds to a human tumor target antigen (TTA) (sdABD-TTA), the sdABD comprising the amino acid sequence of SEQ ID NOs:1, 5, 9, or 13;
b) a first domain linker;
c) a constrained Fv domain comprising:
i) a first variable heavy domain comprising a vhCDR1, vhCDR2 and vhCDR3;
ii) a constrained non-cleavable linker (CNCL); and
iii) a first variable light domain comprising vlCDR1, vlCDR2 and vlCDR3, wherein the CNCL is positioned between the first variable heavy domain and the first variable light domain and prevents the first variable heavy domain and the first variable light domain from interacting to form an active Fv capable of binding CD3;
d) a second domain linker;
e) a second sdABD-TTA, the sdABD comprising the amino acid sequence of SEQ ID NOs:1, 5, 9, or 13;
f) a cleavable linker (CL);
g) a pseudo Fv domain comprising:
i) a first pseudo variable light domain;
ii) a non-cleavable linker (NCL); and
iii) a first pseudo variable heavy domain;
h) a third domain linker; and
i) a third sdABD that binds to human serum albumin;
wherein:
the first variable heavy domain and the first variable light domain are capable of binding human CD3 but said constrained Fv domain does not bind CD3; and the polypeptide does not bind CD3 when the CL is intact (issued claim 1). In some embodiments, the third sdABD that binds to human serum albumin comprises the amino acid sequence of SEQ ID NO:45, corresponding to SEQ ID NO: 45 of the instant claims (issued claim 10).
The issued claims do not recite that the polypeptide (i.e. COBRA construct) is the prodrug Pro186 nor that the cancer is colorectal cancer.
However, May teaches the COBRA polypeptide Pro186 for use in treating cancer in a subject (Para. 0005, Para. 0016, Para. 0276, Claim 13, and Claim 18). Pro186 is an anti-EGFR COBRA comprising an MMP9 cleavable linker and having the amino acid sequence of SEQ ID NO: 145, corresponding SEQ ID NO: 145 of the instant claims (Para. 0055-0056, Para. 0059, Figure 37, and Figure 62B). Pro186 fully comprises the sdABD of SEQ ID NO: 5 (alpha-EGFR2), corresponding to SEQ ID NO: 5 of the instant claims. “Format 2” constructs have the structure set forth in issued claim 1 (and instant claim 1) (see Summary of the Invention, issued specification).
Spano further teaches that epidermal growth factor receptor (EGFR) is overexpressed in many types of cancers, including colorectal cancer, and reflects more aggressive histological and clinical behaviors. In particular, EGFR overexpression in colorectal patients is significantly associated with tumor-node-metastasis stage T3 (Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of the issued claims such that the COBRA construct is substituted with Pro186 and the cancer is a colorectal cancer. One of ordinary skill in the art would have been motivated to do so since colorectal cancer can be characterized by overexpression of EGFR as taught by Spano; as such, the anti-EGFR COBRA construct Pro186 can be used to effectively treat EGFR-expressing tumors. Further, artisans would have been motivated to substitute the EGFR-specific COBRA recited in the issued claims with the EGFR-specific COBRA Pro186 disclosed by May and having the same general structure (“Format 2”) since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Therefore, one of ordinary skill in the art would reasonably expect that the method of the issued claims can be used to effectively treat colorectal cancer in a subject, wherein the COBRA construct is the anti-EGFR COBRA Pro186.
Claim 32 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12478673B2 in view of May and Spano, as applied to claims 1, 3, 18, 36, 38-43, and 58 above, and further in view of Eisenhauer et al (Eisenhauer, E A et al. European journal of cancer (Oxford, England : 1990) vol. 45,2 (2009): 228-47. doi:10.1016/j.ejca.2008.10.026), hereinafter Eisenhauer.
The teachings of the issued claims in view of May and Spano have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the patient has an ECOG performance status of at least grade 1 and/or a measurable disease as per RECIST v1.1 criteria and documented by CT and/or MRI.
However, Eisenhauer teaches that RECIST 1.1 is a standard way to measure the response of a tumor to treatment (Abstract and Background). To assess objective response, it is necessary to estimate the overall tumor burden at baseline and use this as a comparator for subsequent measurements. Only patients with measurable disease at baseline are included in protocols where objective tumor response is the primary endpoint, wherein measurable disease is defined by the presence of at least one measurable lesion (Section 3.1.1 and Section 4.1) and can be determined using, for example, CT or MRI (Section 1.4 and Section 3.1.1).
It would have been obvious to one of ordinary skill in the art to modify the method of treating colorectal cancer taught by the issued claims in view of May and Spano such that the patient administered a COBRA such as Pro186 is one that has a measurable tumor as determined by RECIST 1.1 criteria and documented via CT or MRI assessments. One of ordinary skill in the art would have been motivated to do so because to determine the objective response of a tumor to treatment the patient should have measurable disease at baseline as taught by Eisenhauer. Therefore, one of ordinary skill in the art would reasonably expect that patients having a measurable tumor per RECIST v1.1 criteria represent a population in need of therapeutic intervention (e.g. with the COBRA polypeptide Pro186), while also severing as a cohort for assessing objective treatment response.
Claims 1, 36, 40, and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-42 of copending Application No. 18318218 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims either anticipate or are obvious variants over the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The co-pending claims recite a fusion protein comprising, from N- to C-terminal
a) a first sdABD-TTA;
b) a first domain linker;
c) aco nstrained Fv domain comprising:
i) a first variable heavy domain comprising a vhCDRI,vhCDR2 and vhCDR3;
ii) a constrained non-cleavable linker (CNCL); and
iii) a first variable light domain comprising vlCDRI, vlCDR2 and vlCDR3;
d) a second domain linker;
e) a second sdABD-TTA;
f) a cleavable linker (CL);
g) a constrained pseudo Fv domain comprising:
i) a first pseudo light variable domain;
ii) a non-cleavable linker (NCL); and
iii) a first pseudo heavy variable domain;
h) a third domain linker; and
i) a third sdABD that binds to human serum albumin;
wherein said first variable heavy domain and said first variable light domain are capable of binding human CD3 but said constrained Fv domain does not bind CD3; said first variable heavy domain and said first pseudo variable light domain intramolecularly associate to form an inactive Fv; said first variable light domain and said first pseudo variable heavy domain intramolecularly associate to form an inactive Fv; and wherein at least one of said sdABD-TTA is a sdABD-Trop2 (co-pending claim 23). In some embodiments, the first and second TTA is the same (co-pending claim 36) and the half-life extension domain has the amino acid sequence of SEQ ID NO: 117 (corresponding to SEQ ID NO: 45 of the instant claims) (see below). Further recited is a method of treating cancer comprising administering the fusion protein of claim 23 to a patient (co-pending claim 44). An exemplary fusion protein is Pro676 (co-pending claim 39), which has an MMP9 cleavable linker (see Figure 63J of the co-pending specification).
Thus, the co-pending claims meet the limitations of instant claims 1, 36, 40, and 41.
Half-life Extension Domain: SEQ ID NO: 45 (instant claims) vs SEQ ID NO: 117 (co-pending claims)
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Claim 32 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-42 of copending Application No. 18318218, as applied to claims 1, 36, 40, and 41 above, and further in view of Eisenhauer et al (Eisenhauer, E A et al. European journal of cancer (Oxford, England : 1990) vol. 45,2 (2009): 228-47. doi:10.1016/j.ejca.2008.10.026), hereinafter Eisenhauer.
The teachings of the co-pending claims have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the patient has an ECOG performance status of at least grade 1 and/or a measurable disease as per RECIST v1.1 criteria and documented by CT and/or MRI.
However, Eisenhauer teaches that RECIST 1.1 is a standard way to measure the response of a tumor to treatment (Abstract and Background). To assess objective response, it is necessary to estimate the overall tumor burden at baseline and use this as a comparator for subsequent measurements. Only patients with measurable disease at baseline are included in protocols where objective tumor response is the primary endpoint, wherein measurable disease is defined by the presence of at least one measurable lesion (Section 3.1.1 and Section 4.1) and can be determined using, for example, CT or MRI (Section 1.4 and Section 3.1.1).
It would have been obvious to one of ordinary skill in the art to modify the method of treating cancer taught by the co-pending claims such that the patient administered a COBRA is one that has a measurable tumor as determined by RECIST 1.1 criteria and documented via CT or MRI assessments. One of ordinary skill in the art would have been motivated to do so because to determine the objective response of a tumor to treatment the patient should have measurable disease at baseline as taught by Eisenhauer. Therefore, one of ordinary skill in the art would reasonably expect that patients having a measurable tumor per RECIST v1.1 criteria represent a population in need of therapeutic intervention, while also severing as a cohort for assessing objective treatment response.
Claims 1, 36, 40, and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19 and 56-71 of copending Application No. 18172433 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims either anticipate or are obvious variants over the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The co-pending claims recite a fusion protein comprising, from N-to-C-terminal:
a) a first sdABD that binds HER2 (sdABD-HeR2)
b) a first domain linker;
c) a constrained Fv domain comprising:
i) a first variable heavy domain comprising a vhCDRI,vhCDR2 and vhCDR3;
ii) a constrained non-cleavable linker (CNCL); and
iii) a first variable light domain comprising vlCDRI, vlCDR2 and vlCDR3;
d) a second domain linker;
e) a second sdABD-HER2
f) a cleavable linker (CL);
g) a constrained pseudo Fv domain comprising:
i) a first pseudo light variable domain;
ii) a non-cleavable linker (NCL); and
iii) a first pseudo heavy variable domain;
h) a third domain linker; and
i) a third sdABD that binds to human serum albumin;
wherein said first variable heavy domain and said first variable light domain are capable of binding human CD3 but said constrained pseudo Fv domain does not bind CD3;
the first variable heavy domain and said first pseudo variable light domain intramolecularly associate to form an inactive Fv; and
the first variable light domain and said first pseudo variable heavy domain intramolecularly associate to form an inactive Fv;
wherein the first and/or second sdABD-TTA is a sdABD-HER2 (co-pending claim 56).
In some embodiments, the first and second sdABD-HER2 are the same (co-pending claim 57). The cleavable linker cleaved by a human protease selected from the group consisting of MMP2, MMP9, meprin A, meprin B, cathepsin S, capthepsin K, capthesin L, granzyme B, uPA, kallekrieiny, matriptase, and thrombin (co-pending claim 65). An exemplary fusion protein comprises the amino acid sequence of SEQ ID NO: 478 (co-pending claim 66), which fully comprises the half-life extension domain of SEQ ID NO: 45 recited in the instant claims at positions 765 to 879 (see below). Lastly recited is a method of treating a HER-2 expressing cancer in a subject comprising administering the sdABD (co-pending claim 71).
The fusion protein of SEQ ID NO: 478 fully comprises the half-life extension domain of SEQ ID NO: 45 of the instant claims at positions 765 to 879.
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Claim 32 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19 and 56-71 of copending Application No. 18172433, as applied to claims 1, 36, 40, and 41 above, and further in view of Eisenhauer et al (Eisenhauer, E A et al. European journal of cancer (Oxford, England : 1990) vol. 45,2 (2009): 228-47. doi:10.1016/j.ejca.2008.10.026), hereinafter Eisenhauer.
The teachings of the co-pending claims have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the patient has an ECOG performance status of at least grade 1 and/or a measurable disease as per RECIST v1.1 criteria and documented by CT and/or MRI.
However, Eisenhauer teaches that RECIST 1.1 is a standard way to measure the response of a tumor to treatment (Abstract and Background). To assess objective response, it is necessary to estimate the overall tumor burden at baseline and use this as a comparator for subsequent measurements. Only patients with measurable disease at baseline are included in protocols where objective tumor response is the primary endpoint, wherein measurable disease is defined by the presence of at least one measurable lesion (Section 3.1.1 and Section 4.1) and can be determined using, for example, CT or MRI (Section 1.4 and Section 3.1.1).
It would have been obvious to one of ordinary skill in the art to modify the method of treating cancer taught by the co-pending claims such that the patient administered a COBRA is one that has a measurable tumor as determined by RECIST 1.1 criteria and documented via CT or MRI assessments. One of ordinary skill in the art would have been motivated to do so because to determine the objective response of a tumor to treatment the patient should have measurable disease at baseline as taught by Eisenhauer. Therefore, one of ordinary skill in the art would reasonably expect that patients having a measurable tumor per RECIST v1.1 criteria represent a population in need of therapeutic intervention, while also severing as a cohort for assessing objective treatment response.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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