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 .
DETAILED ACTION
Claims 1-2, 4-6, 10-14, 16-17, 19-20, 22-23, 26-27, and 29 are pending in the instant application.
Restriction Response
Applicant’s election of: A) the anti-RORI antibody CDR set comprises a VH comprising HCDR1-3 and a VL comprising LCDRI-3 selected from: VH SEQ ID NO:7-9 and VL SEQ ID NO: 10-12; B) the following linker:
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wherein Ab represents the point of attachment of the linker to the antibody, and D represents the point of attachment of the linker to the payload moiety; and C) the following payload:
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wherein ~~~ indicates the point of attachment of the payload to the linker, in the reply filed on 4/24/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Rejections – 35 USC § 112(b)
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 11, 13, 16, 23, and 29 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.
Regarding instant claim 11, the difference between the first structure in claim 11 and the third structure in claim 11 on page 11 is unclear. The structures appear to be the same but included twice for the elected species. Thus, the differences of the meets and bounds of one structure defined as
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from another is unclear and the claim is indefinite.
Regarding instant claim 13, the meets and bounds of the CDR region of the claimed heavy chain and light chain are unclear. The claim does not define the exact amino acid residues that comprise the HCDR1-3 and LCDR1-3 of (a) the heavy chain amino acid sequences in SEQ ID NO: 3 and the light chain amino sequences in
SEQ ID NO: 4; or (b) the heavy chain amino acid sequences in SEQ ID NO: 69 and the light chain amino sequences in SEQ ID NO: 70. Thus, the claim is indefinite as to what sequences are required for the HCDR1-3 and LCDR1-3.
Regarding instant claim 16, claim 16 is dependent upon a canceled base claim and is therefore incomplete as there is no antecedent basis for the limitations in the canceled base claims.
MPEP 608.01(n): “If the base claim has been canceled, a claim which is directly or indirectly dependent therein would be rejected as incomplete.”
For the purposes of compact prosecution claim 16 is being examined as dependent on claim 14.
Regarding instant claim 23, claim 23 references Table 3 from the specification. MPEP 2173.05 (s) indicates where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). Thus, the claim is indefinite.
Regarding instant claim 29, the claims list a genus followed by the term “optionally” then describes species of the genus, wherein: 1) a solid tumor, optionally wherein species are further recited; and 2) breast cancer, optionally wherein the breast cancer is triple negative breast cancer. It is not clear whether the recitation of the species are an optionally preferred example—and therefore not limiting—or further limitations of the scope of the claim.
Claim Rejections – 35 USC § 112(a)
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 1-2, 4-6, 12-14, 16-17, 19-20, 22-23, 26-27, and 29 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.
Regarding instant claim 12, an immunoconjugate is claimed wherein the antibody or fragment binds to the same ROR1 epitope as an antibody comprising the heavy chain and light chain amino acid sequences of SEQ ID NOs: 3 and 4, respectively without specifying an amino acid sequence of the antibody the binds to the epitope. Antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites.
Regarding instant claim 5, cysteine drug conjugates produced via partial reduction of interchain disulfide bonds generate up to eight reactive cysteine thiol groups, thus, only n values 1-8 are available for conjugation. Instant claim 5 is dependent on instant claim 1 without including n as a maximum of 8.
Claims 27 and 29 are for methods of treating cancer in a patient in need thereof by administering an antibody drug conjugate wherein the antibody binds ROR1, but the cancer is not required to express the ROR1 target.
Regarding instant claim 1, compound analogs encompass three separate categories: 1) analogs possessing chemical and pharmacological similarities (direct analogs); 2) analogs possessing structural similarities only (structural analogs); and 3) chemically different compounds displaying similar pharmacological properties (functional analogs). The instant specification teaches that an exatecan analog has substantially similar biological profiles as exatecan (specification, page 30-31, [0078]), but the Applicant doesn’t have written description of a genus of exatecan moiety analogs with similar biological profiles of direct analogs, structural analogs, or functional analogs. Claims 2, 4-6, 12-14, 16-17, 19-20, 22-23, 26-27, and 29 are further rejected because they do not narrow the claim outside of the structure of an analog of exatecan.
Scope of the claimed genus
Regarding instant claim 12, an immunoconjugate is claimed wherein the antibody or fragment binds to the same ROR1 epitope as an antibody comprising the heavy chain and light chain amino acid sequences of SEQ ID NOs: 3 and 4, respectively without specifying an amino acid sequence of the antibody the binds to the epitope.
Regarding instant claim 5, an immunoconjugate is claimed, wherein cysteines of the antibody are conjugated to the L-D, wherein an integer of n=1-10 conjugates are attached to the antibody.
Claims 27 and 29 are for methods of treating cancer in a patient in need thereof by administering an antibody drug conjugate wherein the antibody binds ROR1, but the cancer is not required to express the ROR1 target.
Claim 1 claims an immunoconjugate is claimed having the formula Ab-(L-D)n, wherein D is an exatecan moiety or an analog thereof.
Summary of Species disclosed in the original specification
MPEP § 2163 states that 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.
The specification taught ROR1 antibodies comprising 9 sequences in Table 1 (page 18) and ADCs targeting ROR1 expressing cancer cells were effective when administered to a subject in vivo (Fig. 3-4).
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The specification does not teach a structure activity relationship that shows the Applicant has possession of a genus of species for binding the same epitope as an antibody comprising a heavy chain of instant SEQ ID NO:3 and a light chain of instant SEQ ID NO:4. Nine antibodies with several CDR sequences that overlap is not representative of the large number of antibody sequences that have the potential to bind the ROR1 epitope of an antibody comprising a heavy chain of instant SEQ ID NO:3 and a light chain of instant SEQ ID NO:4.
The specification does not teach cysteine conjugated ADCs with a DAR of 9-10.
The instant specification does not teach effective treatment of cancers that do not express ROR1.
The instant specification taught the ADCs ADC-U, ADC-V, ADC-W, and ADC-X comprising an exatecan moiety payload (specification, pages 52-54, Table 2-3) were effective in vitro (specification, pages 65-66, Table 5) and in vivo (Figs. 3-4), but not any other exatecan analogs.
State of the Relevant Art
An anti-ROR1 ADC comprising a heavy chain of instant SEQ ID NO:3 and instant light chain SEQ ID NO:4 is known to the prior art, wherein US 2018/0369406 (Lannutti et al. IDS reference) taught : i) conjugation of Ab1 comprising ‘406 SEQ ID NO:3 and a light chain of ‘406 SEQ ID NO:4 with MC-VC-PAB-MMAE via cysteine residues to form ADC-A, wherein the drug to antibody ratio was about 4 (page 46, [0349-0351]); ii) ADC-A and unconjugated Ab1 effectively targeted ROR1-positive cancer cells ((page 3, [0026] and Fig. 2); and iii) administration of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and ADC-A to a patient with DLBCL that expresses ROR1 was effective (Fig. 12). ‘406 and ADC-A did not show: 1) a structure activity relationship that described the genus of species that would allow a person having ordinary skill in the art to determine the amino acid sequence of an antibody that could bind the same epitope to bind an antibody comprising a heavy chain of ‘406 SEQ ID NO:3 and a light chain of ‘406 SEQ ID NO:4, which is identical to an antibody comprising a heavy chain of instant SEQ ID NO:3 and a light chain of instant SEQ ID NO:4; 2) an effective ADC that was conjugated via cysteine and possessed a DAR > 8; and 3) binding to cancer cells that did not express ROR1.
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
The prior art has taught most ADCs are synthesized by conjugating a cytotoxic compound or “payload” to a monoclonal antibody (Behrens CR et al. (Mol. Pharmaceutics 2015, 12, 11, 3986–3998), page 3986, left column, first paragraph). Behrens taught the payloads are conjugated using amino or sulfhydryl specific linkers that react selectively with lysines or cysteines on the antibody surface, wherein a typical antibody contains over 50 lysines and eight interchain cysteines as potential conjugation sites (page 3986, left column, first paragraph). Behrens taught conjugation through antibody cysteines minimizes ADC heterogeneity relative to lysine conjugation because there are fewer potential conjugation sites (page 3986, right column, first paragraph). The process typically involves partial reduction of four antibody interchain disulfide bonds to generate up to eight reactive cysteine thiol groups, followed by conjugation of payloads containing thiol-specific maleimide linkers (page 3986, right column, first paragraph). Behrens taught ADCs with suboptimal DARs are prone to aggregation, poor solubility, and instability, which often lead to increased toxicity and/or inadequate efficacy in vivo (page 3986, left column, first paragraph). Behrens taught the discrepancy between the number of potential conjugation sites and the desired DAR, combined with the use of linkers that lack site-specificity, results in heterogeneous ADCs that vary in both DAR and the conjugation sites (page 3986, left to right column bridging sentence). Behrens taught consequently, most of the ADCs in clinical development for cancer indications contain dozens or more of chemically distinct ADC molecules, each with unique pharmacological properties (page 3986, right column, first paragraph). Thus, linker-drug conjugates would conjugate up to 8 cysteines on the antibody.
US 2018/0369406 (Lannutti et al. IDS reference) taught : i) conjugation of Ab1 comprising ‘406 SEQ ID NO:3 and a light chain of ‘406 SEQ ID NO:4 with MC-VC-PAB-MMAE via cysteine residues to form ADC-A, wherein administration of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and ADC-A to a patient with DLBCL that expresses ROR1 was effective (Fig. 12). ‘406 did not show ADC-A could bind to cancer cells that did not express ROR1.
Li W taught camptothecin and its derivatives bind to the TOPO 1/DNA complex to prevent reannealing, which can cause cell death due to the accumulation of partially cleaved DNA (Li W et al. (ACS Med Chem Lett. 2019 10(10):1386–1392), page 1386, left column, last paragraph). Li W taught class of compounds has at least five rings (A–E), and in aqueous solution, wherein the E-ring is in equilibrium between the closed and open forms (Fig. 1). Li W taught the E-ring open form is reported to be far less active (page 1386 left to right bridging paragraph). The prior art has also shown that analogs of camptothecin and exatecan can have diminished activity wherein the chiral center located at position 20 of the E-ring with an R-configuration is inactive and elimination of A and B rings causes no discernible inhibition of DNA and RNA synthesis at a µM concentration where camptothecin reached 50% inhibition (Li F et al. Am J Cancer Res. 2017 7(12):2350–2394), 2353, right column, second paragraph). Further, the breadth of exatecan moiety analogs occupy a vast chemical space of not only structural analogs, but non-structural analogs that do not require the exatecan analog to have any structural similarity but only similar biological properties. Thus, the Applicant does not have written description of a genus of exatecan moiety analogs.
Claims 5, 12, 27, and 29 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:
1) an antibody or antigen-binding fragment thereof that binds ROR1 comprising a heavy chain of SEQ ID NO:3 and a light chain of SEQ ID NO:4;
2) an antibody-drug conjugate wherein n is a number between 1 and 8; and
3) a method of treating a cancer in a patient in need thereof, wherein the cancer expresses ROR1,
does not reasonably provide enablement for:
an antibody or antigen-binding fragment thereof that binds the same ROR1 epitope as heavy chain of SEQ ID NO:3 and a light chain of SEQ ID NO:4;
an antibody-drug conjugate wherein n is a number between 9 and 10; and
a method of treating a cancer in a patient in need thereof, wherein the cancer is silent toward the expression of ROR1.
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 the invention commensurate in scope with these claims.
Regarding instant claim 12, an immunoconjugate is claimed wherein the antibody or fragment binds to the same ROR1 epitope as an antibody comprising the heavy chain and light chain amino acid sequences of SEQ ID NOs: 3 and 4, respectively without specifying an amino acid sequence of the antibody the binds to the epitope. Antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites. The specification and prior art do not enable claiming an antibody binding and epitope without a claimed sequence.
Regarding instant claim 5, cysteine drug conjugates produced via partial reduction of interchain disulfide bonds generate up to eight reactive cysteine thiol groups, thus, only n values 1-8 are available for conjugation based on the prior art. Instant claim 5 is dependent on instant claim 1 without including n as a maximum of 8.
Claims 27 and 29 are for methods of treating cancer in a patient in need thereof by administering an antibody drug conjugate wherein the antibody binds ROR1, but the cancer is not required to express the ROR1 target. The specification and prior art do not enable treatment of cancer that does not express ROR1 with treatment of an ROR1 targeted ADC.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These
factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention.
Regarding instant claim 12, an immunoconjugate is claimed wherein the antibody or fragment binds to the same ROR1 epitope as an antibody comprising the heavy chain and light chain amino acid sequences of SEQ ID NOs: 3 and 4, respectively without specifying an amino acid sequence of the antibody the binds to the epitope.
Regarding instant claim 5, an immunoconjugate is claimed, wherein cysteines of the antibody are conjugated to the L-D, wherein an integer of n=1-10 conjugates are attached to the antibody.
Claims 27 and 29 are for methods of treating cancer in a patient in need thereof by administering an antibody drug conjugate wherein the antibody binds ROR1, but the cancer is not required to express the ROR1 target.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
The specification taught ROR1 antibodies comprising 9 sequences in Table 1 (page 18) and ADCs targeting ROR1 expressing cancer cells were effective when administered to a subject in vivo (Fig. 3-4).
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The specification and prior art do not teach a structure activity relationship that shows a genus of species for binding the same epitope as an antibody comprising a heavy chain of instant SEQ ID NO:3 and a light chain of instant SEQ ID NO:4. Nine antibodies with several CDR sequences that overlap is not representative of the large number of antibody sequences that have the potential to bind the ROR1 epitope of an antibody comprising a heavy chain of instant SEQ ID NO:3 and a light chain of instant SEQ ID NO:4.
The specification does not teach cysteine conjugated ADCs with a DAR of 9-10.
The instant specification does not teach effective treatment of cancers that do not express ROR1.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
An anti-ROR1 ADC comprising a heavy chain of instant SEQ ID NO:3 and instant light chain SEQ ID NO:4 is known to the prior art, wherein US 2018/0369406 (Lannutti et al. IDS reference) taught : i) conjugation of Ab1 comprising ‘406 SEQ ID NO:3 and a light chain of ‘406 SEQ ID NO:4 with MC-VC-PAB-MMAE via cysteine residues to form ADC-A, wherein the drug to antibody ratio was about 4 (page 46, [0349-0351]); ii) ADC-A and unconjugated Ab1 effectively targeted ROR1-positive cancer cells ((page 3, [0026] and Fig. 2); and iii) administration of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and ADC-A to a patient with DLBCL that expresses ROR1 was effective (Fig. 12). ‘406 and ADC-A did not show: 1) a structure activity relationship that described the genus of species that would allow a person having ordinary skill in the art to determine the amino acid sequence of an antibody that could bind the same epitope to bind an antibody comprising a heavy chain of ‘406 SEQ ID NO:3 and a light chain of ‘406 SEQ ID NO:4, which is identical to an antibody comprising a heavy chain of instant SEQ ID NO:3 and a light chain of instant SEQ ID NO:4; 2) an effective ADC that was conjugated via cysteine and possessed a DAR > 8; and 3) binding to cancer cells that did not express ROR1.
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
The prior art has taught most ADCs are synthesized by conjugating a cytotoxic compound or “payload” to a monoclonal antibody (Behrens CR et al. (Mol. Pharmaceutics 2015, 12, 11, 3986–3998), page 3986, left column, first paragraph). Behrens taught the payloads are conjugated using amino or sulfhydryl specific linkers that react selectively with lysines or cysteines on the antibody surface, wherein a typical antibody contains over 50 lysines and eight interchain cysteines as potential conjugation sites (page 3986, left column, first paragraph). Behrens taught conjugation through antibody cysteines minimizes ADC heterogeneity relative to lysine conjugation because there are fewer potential conjugation sites (page 3986, right column, first paragraph). The process typically involves partial reduction of four antibody interchain disulfide bonds to generate up to eight reactive cysteine thiol groups, followed by conjugation of payloads containing thiol-specific maleimide linkers (page 3986, right column, first paragraph). Behrens taught ADCs with suboptimal DARs are prone to aggregation, poor solubility, and instability, which often lead to increased toxicity and/or inadequate efficacy in vivo (page 3986, left column, first paragraph). Behrens taught the discrepancy between the number of potential conjugation sites and the desired DAR, combined with the use of linkers that lack site-specificity, results in heterogeneous ADCs that vary in both DAR and the conjugation sites (page 3986, left to right column bridging sentence). Behrens taught consequently, most of the ADCs in clinical development for cancer indications contain dozens or more of chemically distinct ADC molecules, each with unique pharmacological properties (page 3986, right column, first paragraph). Thus, linker-drug conjugates would conjugate up to 8 cysteines on the antibody.
US 2018/0369406 (Lannutti et al. IDS reference) taught : i) conjugation of Ab1 comprising ‘406 SEQ ID NO:3 and a light chain of ‘406 SEQ ID NO:4 with MC-VC-PAB-MMAE via cysteine residues to form ADC-A, wherein administration of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and ADC-A to a patient with DLBCL that expresses ROR1 was effective (Fig. 12). ‘406 did not show ADC-A could bind to cancer cells that did not express ROR1.
Claim Rejections – 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2, 4-6, 10-14, 16-17, 20, 22-23, 26-27, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0369406 (Lannutti et al. IDS reference) and WO 2015/155998 (Hettman T et al.).
‘406 taught : i) conjugation of Ab1 comprising a heavy chain of ‘406 SEQ ID NO:3 and a light chain of ‘406 SEQ ID NO:4 with MC-VC-PAB-MMAE via cysteine residues to form ADC-A, wherein the drug to antibody ratio was about 4 (page 46, [0349-0351]); ii) ADC-A and unconjugated Ab1 effectively targeted ROR1-positive cancer cells ((page 3, [0026] and Fig. 2); and iii) administration of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of ADC-A to a subject with diffuse large B-cell lymphoma (DLBCL) that expresses ROR1 was effective (Fig. 12). ‘406 taught the diffuse large B-cell lymphoma (DLBCL) tumor was a patient-derived xenograft (PDX), thus the DLBCL was a human cancer (Fig. 12 and page 53, [0385-0387]).
‘406 did not teach an ADC comprising a L-D of
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, but this is obvious in view of ‘998.
‘998 taught an immunoconjugate ADC(13) targeting HER3 comprising
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, wherein the drug to antibody ratio was 6.2, wherein the antibody U1-59 targets HER3 (page 160, [0250] and Fig 1-4). ‘998 taught administration of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and ADC(13) to a patient with a cancer that expresses HER3 was effective in vivo (Fig. 14-16).
Regarding instant claims 1-2, 4-6, 10-14, 16-17, 20, 22-23, 26-27, and 29, it would have been obvious for a person having ordinary skill in the art to take the effective method of treating a patient with DLBCL that expresses ROR1 by administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of ADC-A, wherein the drug to antibody ratio was about 4 – and: 1) exchange the linker-drug conjugate L-D of MC-VC-PAB-MMAE for
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of ‘998 and attach it to Ab1; and 2) treat a human patient.
This is obvious because: 1) the linker-drug
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has been shown to be effective at killing target cancer cells; and 2) the ROR1 targeting antibody of Ab1 comprising ‘406 SEQ ID NO:3 and a light chain of ‘406 SEQ ID NO:4 has previously shown to be effective in an ADC at targeting and killing human DLBCL that expresses ROR1.
There is a reasonable expectation of success because: 1) the linker-drug
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has been shown to be effective at killing target cancer cells; and 2) the ROR1 targeting antibody of Ab1 comprising ‘406 SEQ ID NO:3 and a light chain of ‘406 SEQ ID NO:4 has previously shown to be effective in an ADC at targeting and killing DLBCL that expresses ROR1. Thus, the immunoconjugate would be expected to effectively target and kill DLBCL human cancer cells in human patients.
This would produce a method of effectively treating a patient with the cancer diffuse large B-cell lymphoma (DLBCL) (instant claims 27 and 29) that expresses ROR1 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient (instant claim 26) and a therapeutically effective amount of an ADC with the structure of
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(instant claims 6, 10-11, and 23), wherein the L-D is conjugated via a covalent bond to cysteine residues of the antibody (instant claim 5), wherein the linker comprises GGFG which is a cleavable moiety (instant claims 2 and 4), wherein the drug to antibody ratio was about 4 (instant claim 22), wherein Ab1 is an antibody that targets ROR1 comprising a heavy chain of ‘406 SEQ ID NO:3 and a light chain of ‘406 SEQ ID NO:4 which is identical to an antibody comprising a heavy chain of instant SEQ ID NO:3 and a light chain of instant SEQ ID NO:4 (instant claim 20) and further comprises a HCDR1-3 of instant SEQ ID NO:7-9 and a LCDR1-3 of instant SEQ ID NO:10-12 (instant claim 13-14) and a VH of instant SEQ ID NO:5 and a VL of instant SEQ ID NO:6 (instant claim 17), wherein the immunoconjugate would naturally inhibit growth of ROR1+ human cancer cells in vitro with an EC50 of 300 nM or less (instant claim 16) (instant claim 1). An anti-ROR1 antibody identical to an antibody comprising a heavy chain of instant SEQ ID NO:3 and a light chain of instant SEQ ID NO:4 would bind an identical epitope (instant claim 12).
Claims 1-2, 4-6, 10-14, 16-17, 19-20, 22-23, 26-27, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0369406 (Lannutti et al. IDS reference) and WO 2015/155998 (Hettman T et al.) as applied to claims 1-2, 4-6, 10-14, 16-17, 20, 22-23, 26-27, and 29 above, and further in view of Wang X et al. (Protein Cell. 2017 9(1):63–73).
‘406 does not teach the IgG1 constant region comprises an Fc region mutations of L234A and L235A (LALA), but this is obvious in view of Wang.
Wang taught reduced effector function is warranted to prevent antibody-drug conjugates from interacting with FcγRs which can lead to off-target cytotoxicity (page 68, left column, second paragraph). Wang taught administration of an antibody can cause induction of pro-inflammatory cytokines (i.e., cytokine storm) due to interactions with FcγRs and that in order to reduce this unintended effector function the human IgG1 variant L234A/L235A can be effectively used to reduce inflammatory cytokine release (page 68, left column, second paragraph).
Regarding instant claim 19, it would have been obvious for a person having ordinary skill in the art to take the combined method of ‘406 and 998 above – and: 1) include Fc region mutations of L234A and L235A (LALA) in the IgG1 constant region in view of Wang.
This is obvious because: 1a) Wang taught reduced effector function is warranted to prevent antibody-drug conjugates from interacting with FcγRs which can lead to off-target cytotoxicity; and 1b) Wang taught administration of an antibody can cause induction of pro-inflammatory cytokines (i.e., cytokine storm) due to interactions with FcγRs and that in order to reduce this unintended effector function the human IgG1 variant L234A/L235A can be effectively used to reduce inflammatory cytokine release.
There is a reasonable expectation of success because: 1a) Wang taught reduced effector function is warranted to prevent antibody-drug conjugates from interacting with FcγRs which can lead to off-target cytotoxicity; and 1b) Wang taught administration of an antibody can cause induction of pro-inflammatory cytokines (i.e., cytokine storm) due to interactions with FcγRs and that in order to reduce this unintended effector function the human IgG1 variant L234A/L235A can be effectively used to reduce inflammatory cytokine release.
This would produce a method of effectively treating a patient with the cancer diffuse large B-cell lymphoma (DLBCL) that expresses ROR1 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of an ADC with the structure of
PNG
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230
516
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, wherein the L-D is conjugated via a covalent bond to cysteine residues of the antibody, wherein the linker comprises GGFG which is a cleavable moiety, wherein the drug to antibody ratio was about 4, wherein Ab1 is an antibody that targets ROR1 comprising a heavy chain of ‘406 SEQ ID NO:3 and a light chain of ‘406 SEQ ID NO:4, wherein the antibody further includes Fc region mutations of L234A and L235A (LALA) in the IgG1 constant region
(instant claim 19).
Conclusion
Claims 1-2, 4-6, 10-14, 16-17, 19-20, 22-23, 26-27, and 29 are rejected.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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