TDETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-11 and 34-46 are pending and under examination in the instant Office Action.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216. Accordingly, the instant claims are examined with the benefit of the filing date of the PCT application from which the instant 371 Application was filed, 5 August 2022.
Information Disclosure Statement
The information disclosure statement(s) have been considered except where lined through. CN107459678A, CN108347906, CN111801352, CN112745392, CN114057876, and CN114057877 have not been considered because there is no English language abstract or statement of relevance. CN114437227 has been considered because it was reviewed separately in the course of the Examiner’s search and the English-language equivalent is included on the PTO-892.
Claim Objections
Claim 9 is objected to as informal because of the list of broad and narrow limitations recited in the alternate (e.g. “the tumor comprises a benign tumor or cancer [...]; or the hematologic cancer comprises leukemia, acute myeloid leukemia [etc.]”). Although the broad and narrow limitations are recited in the alternate and therefore are not indefinite, the structure of the list is informal and obscures which limitations are required by the claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 4-11, 34-35 and 37-46 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 claim 1, the recitation of “wherein the variable region [...] comprises at least one or more of” VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 allow for changes to the CDR within the VH and VL of the antibody which is the binding determinant region, but the art and genus of known species does not allow for predictable binding of the recited function of binding CD47 or PD-L1.
Scope of the claimed genus
Claims 1 and 34 recite a genus of bispecific antibodies or antigen binding domains thereof comprising an antibody binding fragment which specifically binds to PD-L1 and comprises at least one or more of CDRs SEQ ID NOs: 1-6 and an antibody binding fragment which specifically binds to CD47 and comprises at least one or more of CDRs SEQ ID NOs: 7-9 and 4-6. Therefore, the claims require only one of the CDRs per antigen binding region.
Claims 4 and 37 recite that the PD-L1 domain comprises a VH of SEQ ID NO: 10 or an amino acid sequence having at least 80% or 90% identity to SEQ ID NO: 10, and a VL that comprises SEQ ID NO: 12 or a sequence having at least 80% or 90% identity to SEQ ID NO: 12. Claim 5 and 38 recite that the CD47 domain comprises a comprises a VH of SEQ ID NO: 11 or an amino acid sequence having at least 80% or 90% identity to SEQ ID NO: 11, and a VL that comprises SEQ ID NO: 12 or a sequence having at least 80% or 90% identity to SEQ ID NO: 12. Claims 7 and 40 recite the sequences of the heavy chain constant regions but do not further restrict the sequence of the antigen-binding determinant region. Claims 8 and 41 recite the sequences of the full-length heavy and light chain SEQ ID NOs: 16 or 21; 17 or 22; and SEQ ID NO: 18, or amino acid sequences having at least 80% or 90% identity to SEQ ID NOs: 16 or 21; 17 or 22, and 18.
Dependent claims 2, 6, 9-11, 35, 39, and 42-46 are dependent on claims 1 or 34 without further limiting the structure of the antigen-binding regions.
State of the Relevant Art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 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) teaches 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 teaches 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).
Further, a recitation of “percent identity” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “80% percent identity” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function.
Additionally, 80% identity to the VH of SEQ ID NO: 10 or 11 or VL of SEQ ID NO: 12 would allow 23 amino acid changes to the VHa or VHb and 21 amino acid changes to the VL. This would permit complete exchange of H-CDR1a or b, H-CDR2a or b, H-CDR3a or b, complete exchange of both HCDR1 and HCDR3 for either VHa or VHb, a complete exchange of L-CDR1, CDR2, or CDR3, or complete exchange of any combination of two L-CDRs. The Examiner also notes that the dependent claims recite and/or for the limitations requiring % identity, and therefore there may be complete exchange of either the light chain or the heavy chain in either the anti-PD-L1 or the CD47 binding domains, or both, but for a single CDR.
In regard to anti-CD47 and anti-PD-L1 binding antibodies, other bispecific PD-L1/CD47 antigen binding sites are known in the art and methods of treating cancer are known in the art. For example, Wang et al., "Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity," Cancer Immunology, Immunotherapy, 2021, Vol 70, 12 pages teaches (Of record, IDS 8/29/2025) a method of treating a mouse model reconstituted with human PBMC against Raji-PDL1 or A375 tumors wherein the bispecific antibody IBI322 was superior to a combination of anti-PD-L1 and anti-CD47 monospecific antibodies and the monospecific antibodies alone (Fig. 6). Wang et. al. teaches “A bispecific antibody that targets both CD47 and PD-L1 provides an innovative solution to these problems. PD-L1 is a highly expressed antigen on multiple tumors, and recent studies have demonstrated that CD47 and PD-L1, both activated by oncogenic c-Myc signaling in tumor cells, cooperatively suppressed anti-tumor immune responses [12, 27]. In addition, both PD-L1 and CD47 were co-expressed on tumor cells, whereas most normal cells (e.g. RBCs) had only limited PD-L1 expression [10]. The differential co-expression pattern of CD47 and PD-L1 in tumors versus normal tissues supported the rationale of designing a bispecific antibody that could selectively recognize PD-L1-positive tumor cells and inhibit their CD47 signal to trigger phagocytosis, while sparing cells with no/low PD-L1 expression” (Discussion para. 2).
In addition, WO2019109876 to Liu et. al. published 13 June 2019 also teaches a different anti-PD-L1/anti-CD47 bispecific antibody comprising 2/3 of the anti-PD-L1 heavy chain CDRs (SEQ ID NO: 6, see alignment), but none of the light chain or anti-CD47 heavy chain CDRs.
Thus, it not predictable a priori which changes to the CDRs would result in an antibody that maintains its anti-CD47 and anti-PD-L1 binding functions.
Summary of Species disclosed in the original specification
The instant specification discloses a single genus of bispecific antibodies comprising the CDRs VHa SEQ ID NOs: 1-3, VLa and VLb CDRs SEQ ID NOs: 4-6, and VHb CDRs SEQ ID NOs: 7-9 (e.g. p. 2 through p. 3, top). Two working versions of this antibody are disclosed, BsAb-71 and BsAb-71-N297A, which have identical VH/VL regions (e.g. p. 67; Fig. 1, Fig. 2; Table 1 and Table 2)
One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of variants to allow complete swapping of the VH or VL of the anti-PD-L1 or anti-CD47 domains, substitution of two CDRs in in any of the VH or VL domains, and substitution, addition, or deletion of any amino acid in the anti-PD-L1 and anti-CD47 CDRs up to 80% identity at the narrowest as recited in the instant claims.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for antibody CDR residues for the recited function of binding the proteins CD47 and PD-L1. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; or iii) disrupt protein target binding. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of substitutions and deletions of the polypeptide of claims 1 and 34 at the time of filing. Regarding claims 2, 4-11, 35, and 37-46, the claims are ultimately dependent on the rejected claim 1 or 34 without narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-11 and 42-46 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 a method of treating 1) wherein the disease is cancer and 2) comprising administering an anti-PD-L1 antagonist and anti-CD47 antagonist bispecific antibody wherein each binding domain comprises a complete set of 6 CDRs, does not reasonably provide enablement for a method of treating 1) wherein the disease is any generic autoimmune disease, inflammatory disease, or infectious disease and 2) wherein the PD-L1 variable region comprises at least one CDR of SEQ ID NOs: 1-6 and the CD47 variable region comprises at least one CDR of SEQ ID NOs: 7-9 and 4-6. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
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
The instant claims are directed at a method of treating an autoimmune disease, an inflammatory disease, an infectious disease, or a tumor comprising administering to a patient in need thereof an effective amount of an anti-PD-L1/CD47 bispecific antibody or an antigen-binding fragment; wherein the anti-PD-L1/CD47 bispecific antibody or the antigen-binding fragment wherein the PD-L1 variable region comprises at least one CDR of SEQ ID NOs: 1-6 and the CD47 variable region comprises at least one CDR of SEQ ID NOs: 7-9 and 4-6.
Claim 4 recites that the PD-L1 domain comprises a VH of SEQ ID NO: 10 or an amino acid sequence having at least 80% or 90% identity to SEQ ID NO: 10, and a VL that comprises SEQ ID NO: 12 or a sequence having at least 80% or 90% identity to SEQ ID NO: 12. Claim 5 recites that the CD47 domain comprises a comprises a VH of SEQ ID NO: 11 or an amino acid sequence having at least 80% or 90% identity to SEQ ID NO: 11, and a VL that comprises SEQ ID NO: 12 or a sequence having at least 80% or 90% identity to SEQ ID NO: 12. Claim 7 recites the sequences of the heavy chain constant regions but do not further restrict the sequence of the antigen-binding determinant region. Claim 8 recites the sequences of the full-length heavy and light chain SEQ ID NOs: 16 or 21; 17 or 22; and SEQ ID NO: 18, or amino acid sequences having at least 80% or 90% identity to SEQ ID NOs: 16 or 21; 17 or 22, and 18.
Dependent claims 2, 6, 9-11, 35, 39, and 42-46 are dependent on claims 1 or 34 without further limiting the structure of the antigen-binding regions or the method of treating.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art
Methods of treating comprising administering anti-CD47/anti-PD-L1 antibodies are known in the art. For example, Wang et al., "Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity," Cancer Immunology, Immunotherapy, 2021, Vol 70, 12 pages teaches (Of record, IDS 8/29/2025) a method of treating a mouse model reconstituted with human PBMC against Raji-PDL1 or A375 tumors wherein the bispecific antibody IBI322 was superior to a combination of anti-PD-L1 and anti-CD47 monospecific antibodies and the monospecific antibodies alone (Fig. 6). Wang et. al. teaches “A bispecific antibody that targets both CD47 and PD-L1 provides an innovative solution to these problems. PD-L1 is a highly expressed antigen on multiple tumors, and recent studies have demonstrated that CD47 and PD-L1, both activated by oncogenic c-Myc signaling in tumor cells, cooperatively suppressed anti-tumor immune responses [12, 27]. In addition, both PD-L1 and CD47 were co-expressed on tumor cells, whereas most normal cells (e.g. RBCs) had only limited PD-L1 expression [10]. The differential co-expression pattern of CD47 and PD-L1 in tumors versus normal tissues supported the rationale of designing a bispecific antibody that could selectively recognize PD-L1-positive tumor cells and inhibit their CD47 signal to trigger phagocytosis, while sparing cells with no/low PD-L1 expression” (Discussion para. 2). Wang et. al. teaches that the mechanism through which the anti-CD47 antibodies work is through blocking CD47/SIRP-alpha interactions through which cancer cells evade immune surveillance (Introduction para. 1) and that PD-L1 expression on tumors suppresses tumor-specific immune T cell functions such that anti-PD-L1 antibodies that block PD-1 interaction increase innate immune response to tumors. There is no evidence of record indicating the role of these CD47/PD-L1 pathways in autoimmune disease, inflammatory disease, or infectious disease. Additionally, in both autoimmune disease and inflammatory disease a person of ordinary skill in the art would expect that a CD-47/PD-L1 antagonist bispecific antibody would contribute to increased immune activation and may exacerbate these conditions.
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 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).
Further, a recitation of “percent identity” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “80% percent identity” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function.
Additionally, 80% identity to the VH of SEQ ID NO: 10 or 11 or VL of SEQ ID NO: 12 would allow 23 amino acid changes to the VHa or VHb and 21 amino acid changes to the VL. This would permit complete exchange of H-CDR1a or b, H-CDR2a or b, H-CDR3a or b, complete exchange of both HCDR1 and HCDR3 for either VHa or VHb, a complete exchange of L-CDR1, CDR2, or CDR3, or complete exchange of any combination of two L-CDRs. The Examiner also notes that the dependent claims recite and/or for the limitations requiring % identity, and therefore there may be complete exchange of either the light chain or the heavy chain in either the anti-PD-L1 or the CD47 binding domains, or both.
In regards to anti-CD47 and anti-PD-L1 binding antibodies, other bispecific PD-L1/CD47 antigen binding sites are known in the art and methods of treating cancer are known in the art.
In addition, to Wang et. al. as described in (1) above, WO2019109876 to Liu et. al. published 13 June 2019 also teaches a different anti-PD-L1/anti-CD47 bispecific antibody comprising 2/3 of the anti-PD-L1 heavy chain CDRs (SEQ ID NO: 6, see alignment), but none of the light chain or anti-CD47 heavy chain CDRs.
Thus, the state of the art dose not fill in the deficiencies of the specification in regards to 1) a method of treating autoimmune disease, inflammatory disease, or infectious disease and 2) anti-PD-L1/CD-47 bispecific antibodies comprising less than the instantly described 6 CDRs; it would not have been predictable which antibodies would maintain binding to PD-L1 and CD47, and of these which may have the antagonist PD-1/PD-L1 and CD47/SIRP-alpha blocking functions of the instant example bispecific antibody.
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
The instant specification discloses a single genus of bispecific antibodies comprising the CDRs VHa SEQ ID NOs: 1-3, VLa and VLb CDRs SEQ ID NOs: 4-6, and VHb CDRs SEQ ID NOs: 7-9 (e.g. p. 2 through p. 3, top). Two working versions of this antibody are disclosed, BsAb-71 and BsAb-71-N297A, which have identical VH/VL regions (e.g. p. 67; Fig. 1, Fig. 2; Table 1 and Table 2). The instant specification teaches intraperitoneal administration of the bispecific antibody biweekly to an MC38 colon cancer mouse model (e.g. Example 3) and demonstrate efficacy in reducing tumor volume (e.g. Table 4). The instant specification further discloses pharmacokinetic and toxicological tests in healthy cynomolgus monkeys (e.g. Example 4). Lastly, the specification prophetically discloses a phase Ia/Ib clinical trial evaluating BsAb-71-N297A using a dose escalation study from 0.1 mg/kg to 40 mg/kg (e.g. p. 95 top); phase Ib with dose extension includes i.v. administration every 2 weeks using a 3 + 3 dose escalation starting at 1 mg/kg (Example 5). There are no other antibody variants and no autoimmune diseases, inflammatory diseases, or infectious diseases tested.
Conclusion
Applicant does not have enablement for a method of treating 1) autoimmune diseases, inflammatory diseases, or infectious diseases tested and 2) comprising administering an antibody comprising at least one CDR of SEQ ID NOs: 1-6 and the CD47 variable region comprises at least one CDR of SEQ ID NOs: 7-9 and 4-6. It would take undue experimentation to determine which autoimmune diseases, inflammatory disease, or infectious diseases can be treated and which antibodies meeting the limitations of the instant claims bind CD47 and PD-L1 and have the same blocking functions as the instantly claimed antibody binding domains.
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 1-9, 34-41, and 46 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by CN114437227 to Chen et. al. published 6 May 2022 (Of record, IDS 2/5/2024) and effectively filed 6 November 2020 (citations are to the Google machine translation).
Chen et. al. teaches a bispecific antibody comprising an anti-PD-L1 and an anti-CD47 binding domain comprising an anti-PD-L1 heavy chain SEQ ID NO: 92 (100% identical to instant SEQ ID NO: 16 (instant claims 8 and 41), comprising CDRs of SEQ ID NO 1, 2, and 3 (instant claims 1, 3, 34, and 36); a VH of SEQ ID NO: 10 (instant claim 4 and 37); a CH region of SEQ ID NO: 13 (instant claims 7 and 40)), an anti-CD47 heavy chain SEQ ID NO: 93 (100% identical to instant SEQ ID NO: 17 (instant claims 8 and 41), comprising CDRs of SEQ ID NOs: 7, 8, and 9 (instant claims 1, 3, 34, and 36); a VH of SEQ ID NO: 11 (instant claims 5 and 38); and a CH region of SEQ ID NO: 15 (instant claims 7 and 40)), and a light chain SEQ ID NO: 96 (100% identical to instant SEQ ID NO: 18 (instant claims 8 and 41), comprising CDRs of SEQ ID NOs: 4, 5, and 6 (instant claims 1, 3, 34, and 36); a VL of SEQ ID NO: 12 (instant claims 4-5 and 37-38) to pair with both heavy chains (Example 2.3.1). Chen et. al. teaches a method of treating with the bispecific antibody that the specific dose and treatment will be decided by a medical professional but can be in the range of 0.01 mg/kg to about 100 mg/kg (instant claims 1, 44-45) and can be in the range from twice weekly to monthly (p. 24 para. 2; reads on “once every two days to once every six weeks”; instant claims 1). Chen et. al. teaches a method of treating a C57BL6 mouse model of colon cancer (MC38 cells)(reads on a patient in need; instant specification defines ‘patient’ as any mammal; p. 80; reads on instant claim 9, cancer) comprising administering the PD-L1/CD-47 bispecific with 10mg/kg biweekly X 5. Chen et. al. teaches that the tumor inhibition rate of the 10 mg/kg anti-PD-L1/CD47 bispecific antibody is 68.7% and is superior to the single drug control. Chen et. al. also teaches kits comprising the bispecific (p. 11, middle of the page); the antibody administered in this case reads on the instant “kit” with written instructions because as described in MPEP §2112.01 “the content of the printed matter will not distinguish the claimed product from the prior art” (instant claim 34).
Regarding claims 2 and 35, Chen et. al. teaches that the affinity of the antibody to PD-L1 is greater than the affinity to CD47 (p. 16; p. 19, bottom).
Regarding claims 6 and 39, Chen et. al. teaches wherein the antibody heavy chain constant region comprises the mutation N297A according to EU numbering (p. 3, first paragraph, p. 9 middle).
Regarding claim 46, Chen et. al. teaches that the modes of administration of the antibodies include intravenous (e.g. p. 24 para. 3).
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.
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.
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 10, 11, and 42-45 are rejected under 35 U.S.C. 103 as being unpatentable over CN114437227 to Chen et. al. published 6 May 2022 and effectively filed 6 November 2020 (citations are to the Google machine translation) in view of WO2019068302 to Solovyev et. al. published 11 April 2019 (citations are to the machine translation).
The teachings of Chen et. al. in regard to claims 1 and 34 are in the 102 rejection above.
Regarding claims 10, 11, 44, and 45 Chen et. al. does not explicitly teach the method wherein one treatment cycle is about two weeks to four weeks, or wherein the bispecific antibody fragment is administered once about every two weeks, about every three weeks, or about every four weeks; or wherein the treatment in the dose range or about the recited doses by weight (e.g. about 10 mg/kg about every two weeks, three weeks, or four weeks). The instant specification does not define “about”. The Examiner is interpreting “about” as in the art to mean within 50% of the recited value (e.g. about every two weeks is in between every one week and every three weeks).
Regarding claims 42 and 43, Chen et. al. does not explicitly teach the method wherein the bispecific is administered in a dose of about 210 mg to 700 mg, about 700 mg to 1400 mg (claim 42) or wherein the bispecific is administered at a dose of e.g. about 380 mg, about 700 mg, or of about 1150 mg (claim 43) about every two weeks, three weeks, or four weeks.
Solovyev et. al. teaches a method of administering an antibody specific to CD47 and PD-L1 to treat a subject or patient, wherein is preferably a human subject (p. 21 bottom para) for the treatment of disorders that are mediated by CD47 and PD-L1 for example, subtypes of cancer (p. 3 para. 4) by administering a dose that can be determined by a skilled artisan between 0.1-200 mg/kg, preferably at least .25 mg/kg to 5 mg/kg and up to a maximum of 50 mg/kg or 15mg/kg once every two weeks, once every three weeks, or once every four weeks as deemed necessary by a doctor (p. 43 para. 2).
Regarding claims 42 and 43, the average human is approximately 75 kg, and therefore a dose of at least 5mg/kg is a 375 mg dose (reads on about 210 to 700mg and about 380 mg) and a maximum dose of 15mg/kg is 1125 mg dose (reads on about 700 to 1400 mg and about 1150 mg).
It would have been obvious, as of the effective filing date, for a person of ordinary skill in the art to administer the antibody of Chen within the range of every two days to every six weeks as taught by Chen, in the narrower interval of every two weeks, every three weeks, or every four weeks as taught by Solovyev in order to benefit from the general knowledge of dose timing presumed to be an effective range for a similar CD47 blocking/PD-L1 blocking bispecific antibody, for example to treat the preferred patient of a human rather than a mouse. This would have a reasonable expectation of success because a person of ordinary skill in the art is able to determine the dose and interval of the antibody as taught by Solovyev, which would naturally lead to the cycle lengths and intervals as taught in the instant claims.
In addition, in regard to the specific dosage and interval timing recited in the instant claims "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens.
Claims 1-11 and 34-46 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019109876 to Liu et. al. published 13 June 2019 (citations are to machine translation) in view of WO2021032174 to Grosveld et. al. published 25 February 2021 (citations are to the machine translation) and WO2019068302 to Solovyev et. al. published 11 April 2019 (citations are to the machine translation).
Liu et. al. teaches an anti-PD-L1/anti-CD-47 bispecific antibody in an IgG format (Abstract) wherein the anti-PD-L1 half-antibody portion comprises a VH of SEQ ID NO: 6 and a VL of SEQ ID NO: 2, wherein SEQ ID NO: 6 comprises CDRs identical to instant SEQ ID NOs: 1 and 3 (instant claims 1, 3, 34, and 36; comprises a variable region a specifically binding to PD-L1; comprises at least one or more of VHa CDR 1 SEQ ID NO: 1):
Sequence Length: 118;
Hits at: 26-35
1 EVQLVESGGG LVQPGGSLRL SCAASGFTFS DSWIHWVRQA PGKGLEWVAW ISPYGGSTYY
===== =====
61 ADSVKGRFTI SADTSKNTAY LQMNSLRAED TAVYYCARRH WPGGFDYWGQ GTLVTVSA
ALIGNMENT FROM L-NUMBER L3
Sequence Length: 118;
Hits at: 99-107
61 ADSVKGRFTI SADTSKNTAY LQMNSLRAED TAVYYCARRH WPGGFDYWGQ GTLVTVSA
== =======
The full-length anti-PD-L1 heavy chain comprises VH SEQ ID NO: 6 and CH SEQ ID NO: 8, which combined are 97.7% identical to instant SEQ ID NO: 16 (instant claims 8 and 41)(comprising at least 90% identity to SEQ ID NO 10; instant claims 4 and 37) and a light chain of VL SEQ ID NO: 2 and CL SEQ ID NO: 4, which combined are 90.8% identical to instant SEQ ID NO: 18 (instant claims 8 and 41)
RESULT 1
AASEQ2_07082026_152706
Query Match 97.7%; Score 2368; DB 1; Length 448;
Best Local Similarity 98.2%;
Matches 440; Conservative 2; Mismatches 6; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVGWISPYGGSTYY 60
|||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYY 60
Qy 61 ADSYRSRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSAS 120
||| : |||||||||||||||||||||||||||||||||||||||||||||||||||:||
Db 61 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSAAS 120
Qy 121 TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 180
Qy 181 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS 240
Qy 241 VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYAST 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYAST 300
Qy 301 YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELT 360
|||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||
Db 301 YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT 360
Qy 361 KNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ 420
|||||| |||||||||||||||||||||||||||||||| ||||||||||||||||||||
Db 361 KNQVSLLCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLRSDGSFFLYSKLTVDKSRWQQ 420
Qy 421 GNVFSCSVMHEALHNHYTQKSLSLSPGK 448
||||||||||||||||||||||||||||
Db 421 GNVFSCSVMHEALHNHYTQKSLSLSPGK 448
RESULT 1
AASEQ2_07082026_153625
Query Match 90.8%; Score 1002; DB 1; Length 214;
Best Local Similarity 91.1%;
Matches 195; Conservative 7; Mismatches 12; Indels 0; Gaps 0;
Qy 1 EIVLTQSPSSLSASVGDRVTITCLASQTIGTWLAWYQQKPGKSPQLLIYAASTLQSGVPS 60
:| :||||||||||||||||||| ||| : | :|||||||||:|:||||:|| | |||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDVATYYCQQYYSTPRTFGQGTKVEIKRTVAAPSVFIFPP 120
|||||||||||||||||||||| |||||||| | ||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPP 120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Liu et. al. further teaches that the CD47 binding domain comprises a heavy chain constant region SEQ ID NO: 14, which is 98% identical to instant SEQ ID NO: 15 (instant claims 7 and 40):
RESULT 1
AASEQ2_07082026_154230
Query Match 98.0%; Score 1727; DB 1; Length 330;
Best Local Similarity 98.2%;
Matches 324; Conservative 2; Mismatches 4; Indels 0; Gaps 0;
Qy 1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
Qy 61 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG 120
Qy 121 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA 180
Qy 181 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDE 240
||||||||||||||||||||||||||||||||||||||||||||||||||| | ||||||
Db 181 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTEPPSRDE 240
Qy 241 LTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRW 300
||||||||:| ||||||||||||||||||||||||||||||||||||||:| ||||||||
Db 241 LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLLSVLTVDKSRW 300
Qy 301 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 330
||||||||||||||||||||||||||||||
Db 301 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 330
Liu et. al. teaches that one aspect of the invention is a method of preventing and/or treating disease comprising administering the heterodimeric antibody of the invention wherein the subject is a human subject and the disease is selected from a list of cancer subtypes, including hematolgoic cancer (See e.g. p. 7 para. 5-7)(reads on claims 1 and 9).
Regarding claims 2 and 35, Liu et. al. teaches that the anti-PD-L1 portion of the bispecific has an affinity similar to the monoclonal antibody of 0.118 nM (Fig. 9)
Regarding claims 6 and 39, Liu et. al. teaches wherein the Fc domain comprises the N297A mutation (p. 17, last para.).
Liu et. al. does not teach wherein the anti-CD47 binding domain comprises at least one CDR of SEQ ID NOs: 4, 5, and 6 and 7, 8, and 9 or wherein the bispecific antibody is administered once every two days to once every six weeks at a dose of 0.1mg/kg to 100mg/kg or at a dose of 6mg to 3000mg per treatment cycle.
This deficiency is partially resolved by Grosveld et. al.
Grosveld teaches an anti-CD47 antigen binding protein comprising a VH of SEQ ID NO: 81, which is 90.4% identical to instant SEQ ID NO: 11 (instant claims 5 and 38) and comprising instant CDR SEQ ID NO: 8 (instant claims 1, 3, 34 and 36):
RESULT 1
AASEQ2_07082026_160319
Query Match 90.4%; Score 558.5; DB 1; Length 114;
Best Local Similarity 93.0%;
Matches 107; Conservative 3; Mismatches 4; Indels 1; Gaps 1;
Qy 1 QVQLQESGPGLVKPSETLSLTCTVSGGSLDNYYWSWIRQPPGKGLEWIGYIYYSGNTNYN 60
||||||||||||||||||||||||||||::||||||||||||||||||||||||||||||
Db 1 QVQLQESGPGLVKPSETLSLTCTVSGGSINNYYWSWIRQPPGKGLEWIGYIYYSGNTNYN 60
Qy 61 PSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGRFLERYWGQGTLVTVS 115
||||||||||||||||||||||||||||||||||||| |: |||||||||||
Db 61 PSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARKRGVLD-YWGQGTLVTVS 114
Grosveld teaches that the VL of the anti-CD47 antibody is SEQ ID NO: 15, which is 81.4% identical to instant VL SEQ ID NO: 12 (instant claims 4-5 and 37-38):
Query Match 81.4%; Score 448.5; DB 1; Length 108;
Best Local Similarity 79.6%;
Matches 86; Conservative 14; Mismatches 7; Indels 1; Gaps 1;
Qy 1 EIVLTQSPSSLSASVGDRVTITCLASQTIGTWLAWYQQKPGKSPQLLIYAASTLQSGVPS 60
:| :|||||:||||||||||||| |||:| :|||||||||||:|:|||| ||:|:|||||
Db 1 DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDVATYYCQQYYS-TPRTFGQGTKVEIK 107
|||||||||:||||||||||:| |||||:|| | :| |||||||:|||
Db 61 RFSGSGSGTEFTLTISSLQPDDFATYYCRQYNSYSPYTFGQGTKLEIK 108
Regarding claims 1, 9, and 44-45, Grosveld further teaches that the anti-CD47 binding domain is effective for treating cancer (Abstract) by administering the instant anti-CD47 antibody. Grosveld teaches that the anti-CD47 antibodies have anti-tumor activity in a Raji mouse model in vivo when administered at doses of 1mg/kg and 3mg/kg (Example 11.1) and in an MC38 colon cancer mouse model at 5mg/kg and 10mg/kg (11.2). Grosveld also teaches that the anti-CD47 binding domain may be used in an anti-CD47 bispecific antibody (p. 8 para. 5).
Regarding claims 2 and 35, Grosveld teaches that the binding affinity of the CD47 anti-CD47 binding domain comprising SEQ ID NO: 81, PR001268 is 0.19 nM (reads on lower affinity than the anti-PD-L1 binding domain of Liu, 0.118 nM).
It would have been obvious, as of the effective filing date, to substitute the anti-CD47 domain of Liu et. al. in the anti-PD-L1/CD-47 bispecific for the art-equivalent anti-CD47 binding domain of Grosveld in order to benefit from the anti-cancer CD-47 blocking activity as taught by Grosveld in the anti-PD-L1/CD-47 bispecific format as taught by Liu et. al. This would have a reasonable expectation of success because both Liu et. al. and Grosveld et. al. teaches anti-CD47 antibodies to increase phagocytosis and improve cancer therapy. Substitution of the anti-CD47 VH and VL of Grosveld onto the CH and CL domains of Liu results in a half-antibody anti-CD47 heavy and light chain of the following sequences (95.5% and 90.7% identical to SEQ ID NO: 17 and SEQ ID NO: 18, respectively):
RESULT 1
AASEQ2_07082026_162958
Query Match 95.5%; Score 2275; DB 1; Length 444;
Best Local Similarity 96.6%;
Matches 431; Conservative 5; Mismatches 8; Indels 2; Gaps 2;
Qy 1 QVQLQESGPGLVKPSETLSLTCTVSGGSLDNYYWSWIRQPPGKGLEWIGYIYYSGNTNYN 60
||||||||||||||||||||||||||||::||||||||||||||||||||||||||||||
Db 1 QVQLQESGPGLVKPSETLSLTCTVSGGSINNYYWSWIRQPPGKGLEWIGYIYYSGNTNYN 60
Qy 61 PSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGRFLERYWGQGTLVTVSSASTK 120
||||||||||||||||||||||||||||||||||||| |: |||||||||| |||||
Db 61 PSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARKRGVLD-YWGQGTLVTV-SASTK 118
Qy 121 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 119 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 178
Qy 181 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 179 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF 238
Qy 241 LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYR 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 239 LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYR 298
Qy 301 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKN 360
||||||||||||||||||||||||||||||||||||||||||||||| | ||||||||||
Db 299 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTEPPSRDELTKN 358
Qy 361 QVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGN 420
||||:| ||||||||||||||||||||||||||||||||||||||:| ||||||||||||
Db 359 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLLSVLTVDKSRWQQGN 418
Qy 421 VFSCSVMHEALHNHYTQKSLSLSPGK 446
||||||||||||||||||||||||||
Db 419 VFSCSVMHEALHNHYTQKSLSLSPGK 444
RESULT 1
AASEQ2_07082026_163120
Query Match 90.7%; Score 1001.5; DB 1; Length 215;
Best Local Similarity 89.8%;
Matches 193; Conservative 14; Mismatches 7; Indels 1; Gaps 1;
Qy 1 EIVLTQSPSSLSASVGDRVTITCLASQTIGTWLAWYQQKPGKSPQLLIYAASTLQSGVPS 60
:| :|||||:||||||||||||| |||:| :|||||||||||:|:|||| ||:|:|||||
Db 1 DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDVATYYCQQYYS-TPRTFGQGTKVEIKRTVAAPSVFIFP 119
|||||||||:||||||||||:| |||||:|| | :| |||||||:|||||||||||||||
Db 61 RFSGSGSGTEFTLTISSLQPDDFATYYCRQYNSYSPYTFGQGTKLEIKRTVAAPSVFIFP 120
Qy 120 PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL 179
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL 180
Qy 180 TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
|||||||||||||||||||||||||||||||||||
Db 181 TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 215
Regarding claims 1, 10-11, and 42-45, Liu in view of Grosveld does not teach the dose timing or total dose amounts of the anti-PD-L1/anti-CD-47 antibody. This deficiency is resolved by Solovyev et. al.
Solovyev et. al. teaches a method of administering an antibody specific to CD47 and PD-L1 to treat a subject or patient, wherein is preferably a human subject (p. 21 bottom para) for the treatment of disorders that are mediated by CD47 and PD-L1 for example, subtypes of cancer (p. 3 para. 4) by administering a dose that can be determined by a skilled artisan between 0.1-200 mg/kg, preferably at least .25 mg/kg to 5 mg/kg and up to a maximum of 50 mg/kg or 15mg/kg once every two weeks, once every three weeks, or once every four weeks as deemed necessary by a doctor (p. 43 para. 2) (reads on claims 1, 10, 11, and 44-45).
Regarding claims 42 and 43, the average human is approximately 75 kg, and therefore a dose of at least 5mg/kg is a 375 mg dose (reads on about 210 to 700mg and about 380 mg) and a maximum dose of 15mg/kg is 1125 mg dose (reads on about 700 to 1400 mg and about 1150 mg).
Regarding claim 46, Solovyev teaches that a preferred method of administration is intravenous (p. 37, last para.).
It would have been obvious, as of the effective filing date, for a person of ordinary skill in the art to administer the antibody of Liu in view of Grosveld in the interval of every two weeks, every three weeks, or every four weeks as taught by Solovyev in order to benefit from the general knowledge of dose timing presumed to be an effective range for a similar CD47 blocking/PD-L1 blocking bispecific antibody. This would have a reasonable expectation of success because a person of ordinary skill in the art is able to determine the dose and interval of the antibody as taught by Solovyev, which would naturally lead to the cycle lengths and intervals as taught in the instant claims.
In addition, in regard to the specific dosage and interval timing recited in the instant claims "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens.
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.
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Claims 34-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-20 of copending Application No. 18035591 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of '591 anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of the ‘591 application teach a bispecific antibody comprising a variable region specifically binding PD-L1 and a variable region specifically binding CD47, wherein the PD-L1 variable region comprises any of SEQ ID NOs: 49-63 (SEQ ID NO: 54 is 100% identical to instant SEQ ID NO: 10; instant claims 34-37) and wherein the VL comprises any of SEQ ID NOs: 75-80 (SEQ ID NO: 75 is 100% identical to instant SEQ ID NO: 12; instant claims 37-38) and wherein the anti-CD47 variable region comprises a VH of SEQ ID NO: 64-74 (SEQ ID NO: 64 is 100% identical to instant SEQ ID NO: 11 and comprises a VL of SEQ ID NOs: 75-80 (SEQ ID NO: 75 is 100% identical to instant SEQ ID NO: 12) (instant claim 38); claims 13 and 14 teach wherein the heavy chain constant region comprises an N297A mutation (instant claim 39); claims 15-17 teach the constant regions and the full-length antibody sequences of SEQ ID NO: 92 (100% identical to instant SEQ ID NO: 16); SEQ ID NO: 93 (100% identical to instant SEQ ID NO: 17) and light chain SEQ ID NO: 96 (100% identical to instant SEQ ID NO: 18) and comprising CH and CL regions identical to the instant claims (instant claims 40-41). Claim 19 teaches a composition comprising the antibody and a pharmaceutically acceptable carrier (reads on the instant kit). The antibody composition in this case reads on the instant “kit” with written instructions because as described in MPEP §2112.01 “the content of the printed matter will not distinguish the claimed product from the prior art” (instant claim 34). Regarding claim 35, an antibody with identical binding domains to the instant binding domains would have identical affinity properties.
Claims 1-11 and 42-46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-20 of copending Application No. 18035591 in view of WO2019068302 to Solovyev et. al. published 11 April 2019 (citations are to the machine translation).
This is a provisional nonstatutory double patenting rejection.
The claims of the ‘591 application teach a bispecific antibody comprising a variable region specfically binding PD-L1 and a variable region specifically binding CD47, wherein the PD-L1 variable region comprises any of SEQ ID NOs: 49-63 (SEQ ID NO: 54 is 100% identical to instant SEQ ID NO: 10; instant claims 1, 3, 4) and wherein the VL comprises any of SEQ ID NOs: 75-80 (SEQ ID NO: 75 is 100% identical to instant SEQ ID NO: 12; instant claims 1-5) and wherein the anti-CD47 variable region comprises a VH of SEQ ID NO: 64-74 (SEQ ID NO: 64 is 100% identical to instant SEQ ID NO: 11 (instant claims 1, 3, 5) and comprises a VL of SEQ ID NOs: 75-80 (SEQ ID NO: 75 is 100% identical to instant SEQ ID NO: 12); claims 13 and 14 teach wherein the heavy chain constant region comprises an N297A mutation (instant claim 6); claims 15-17 teach the constant regions and the full-length antibody sequences of SEQ ID NO: 92 (100% identical to instant SEQ ID NO: 16); SEQ ID NO: 93 (100% identical to instant SEQ ID NO: 17) and light chain SEQ ID NO: 96 (100% identical to instant SEQ ID NO: 18) and comprising CH and CL regions identical to the instant claims (instant claims 7-8 and 39). Claim 20 teaches a method for treating a disease in a patient comprising administering to a patient an effective amount of the antibody wherein the disease is a disorder associated with PD-L1 and CD47 and the disease is colon cancer, breast cancer, lung cancer, or melanoma (claims 1 and 9).
Regarding claim 2, an antibody with identical binding domains to the instant binding domains would have identical affinity properties.
The claims of ‘591 do not teach the exact dose amounts or timing of the instant claims (claims 1, 10-11, and 42-45) . This deficiency is resolved by Solovyev. Solovyev et. al. teaches a method of administering an antibody specific to CD47 and PD-L1 to treat a subject or patient, wherein is preferably a human subject (p. 21 bottom para) for the treatment of disorders that are mediated by CD47 and PD-L1 for example, subtypes of cancer (p. 3 para. 4) by administering a dose that can be determined by a skilled artisan between 0.1-200 mg/kg, preferably at least .25 mg/kg to 5 mg/kg and up to a maximum of 50 mg/kg or 15mg/kg once every two weeks, once every three weeks, or once every four weeks as deemed necessary by a doctor (p. 43 para. 2).
Regarding claims 42 and 44, the average human is approximately 75 kg, and therefore a dose of at least 5mg/kg is a 375 mg dose (reads on about 210 to 700mg and about 380 mg) and a maximum dose of 15mg/kg is 1125 mg dose (reads on about 700 to 1400 mg and about 1150 mg).
Regarding claim 46, Solovyev teaches that a preferred method of administration is intravenous (p. 37, last para.).
It would have been obvious, as of the effective filing date, for a person of ordinary skill in the art to administer the antibody of '591 and the method of treating of ‘591 in the interval of every two weeks, every three weeks, or every four weeks as taught by Solovyev in order to benefit from the general knowledge of dose timing presumed to be an effective range for a similar CD47 blocking/PD-L1 blocking bispecific antibody. This would have a reasonable expectation of success because a person of ordinary skill in the art is able to determine the dose and interval of the antibody as taught by Solovyev, which would naturally lead to the cycle lengths and intervals as taught in the instant claims.
In addition, in regard to the specific dosage and interval timing recited in the instant claims "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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