DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
The amended claims filed February 23, 2024 are acknowledged. Claims 2-6, 9, 12-16, and 18 are amended. Claims 1-18 are pending and under examination herein.
It is noted that a Power of Attorney is not on record for the instant application. The
Applicant is encouraged to file a Power of Attorney in the event that the Examiner needs to
communicate with an authorized representative for the Applicant during the prosecution of the
case.
Claim Objections
Claim 9 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim must refer back in the alternative only, cannot refer back to another multiple dependent claim (i.e., claim 8), and cannot refer to two separate claims with different features. See MPEP § 608.01(n).
Claim 12 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim must refer back in the alternative only and cannot refer to two separate claims with different features. See MPEP § 608.01(n).
Accordingly, claims 9 and 12 have not been further treated on the merits.
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 1-8, 10-11, and 13-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1-8, 10-11, 14, and 17-18, the phrases “preferably”, “more preferably”, “further preferably”, and “most preferably” throughout the claims render the claims indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention. See MPEP § 2173.05(d). Examples and preferences in a claim may lead to confusion over the intended scope of the claim. The description of examples or preferences is properly set forth in the specification rather than the claims.
Claims 15-16, which depend from claims 14 and 10, respectively, and do not remedy this deficiency, are similarly rejected.
It is noted for Applicant that limitations which are “preferred” will not be considered as being required for the purpose of applying prior art under 35 U.S.C. § 102 and 103.
Further regarding claim 5, the claim recites that the antibody of claim 1 is “a murine antibody” or, more preferably, “a fully human antibody.” These limitations render the claim unclear because a “murine antibody” is derived from mouse, whereas a “fully human antibody” is derived from a human source and does not contain any murine sequences. See, for example, Harding (MAbs (2010) 2(3): 256-265) at page 258. Murine sequences are immunogenic to humans, and murine-derived CDRs can be engrafted into human sequence-derived framework regions to produce humanized antibodies (Harding, page 258). The specification discloses that the antibodies of the invention were generated using a bacteriophage display library (e.g., Example 1, pages 20-21) and that the 10 Fab antibodies obtained in Example 1 were “fully human” (e.g., Example 2, page 21). Accordingly, it is unclear how the instantly claimed antibodies can be murine antibodies while comprising the apparently human CDR sequences that are recited in claim 1.
It is further noted for Applicant that while claim 5 recites a “single-domain antibody”, the exemplary antibodies disclosed in the specification comprise a heavy chain variable region and a light chain variable region, and thus do not fall under the standard definition of a “single-domain antibody” as understood by those of ordinary skill in the art.
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.
(1)
Claims 1, 3-8, and 13 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.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The claimed invention. The nature and scope of the claimed invention first at issue is an antibody or antigen-binding fragment thereof capable of specifically binding to CD47 (as set forth in claim 1 and dependent claims 3-8), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1 comprising a sequence having one or more amino acid substitutions, deletions, or additions relative to SEQ ID NO: 17, a VH CDR2 comprising a sequence having one or more amino acid substitutions, deletions, or additions relative to SEQ ID NO: 18, and a VH CDR3 comprising a sequence having one or more amino acid substitutions, deletions, or additions relative to SEQ ID NO: 19, and/or a light chain variable region (VL) comprising a VL CDR1 comprising a sequence having one or more amino acid substitutions, deletions, or additions relative to “any one of” SEQ ID NOs: 11, 14, or 22, a VL CDR2 comprising a sequence having one or more amino acid substitutions, deletions, or additions relative to “any one of” SEQ ID NOs: 12, 15, or 23, and a VL CDR3 comprising a sequence having one or more amino acid substitutions, deletions, or additions relative to “any one of” SEQ ID NOs: 13, 16, or 24. Claim 3 further recites that the VH comprises “one or more amino acid substitutions, deletions, or additions compared to the sequence shown in SEQ ID NO: 9” or has a sequence identity of “at least 80%” to “at least 99%” with the sequence shown in SEQ ID NO: 9, and/or a VL comprising an amino acid sequence that comprises “one or more amino acid substitutions, deletions, or additions compared to the sequence shown in any one of SEQ ID NO: 5, SEQ ID NO: 7, or SEQ ID NO: 25” or has a sequence identity of “at least 80%” to “at least 99%” with any one of these VL sequences.
These limitations fail to satisfy the written description requirement for several reasons. First, the claims define the binding domains by their ability to bind to a respective antigen (CD47), but the corresponding structures in the claim that are responsible for conferring this function (i.e., the VH and VL CDRs) are incompletely defined. In particular, the individual CDRs within the VH and/or the VL may comprise variation in their sequences (as understood from “amino acid substitutions, deletions, and additions”) which would be expected to impact the antigen-binding activity of the claimed antibodies. This incompletely defined structure (amino acid sequence) is not sufficient for carrying out the instantly claimed functions based on what is understood in the art and in view of the teachings of Applicant's disclosure. Second, the recitation of “and/or” with respect to the VH and VL CDRs allows that the critical antigen-binding structure for one of the variable domains, but not the other, may be completely undefined by the claim. However, as set forth below, the recitation of a complete antigen-binding structure (VH CDRs and VL CDRs) is required for conventional antibodies to establish sufficient written description support. Third, the language of the claim allows for “mixing and matching” of the first, second, and third VL CDRs. However, not all possible combinations of the CDRs would be expected to result in a functional antigen binding protein as required by the instant claims except for those specifically enumerated in the disclosure.
Secondly at issue is the recombinant oncolytic virus of claim 13, which comprises a gene coding sequence “having a sequence identity of at least 90%, 91%, … or 99% with the sequence shown in SEQ ID NO: 1 or 3”. According to Applicant's disclosure, the nucleotide sequence of SEQ ID NO: 1 corresponds to an anti-CD47 antibody fused to a modified Fc fragment comprising the “ALIE” mutations of A330L and I332E (e.g., ¶ 0043, 0053, 0056), and the nucleotide sequence of SEQ ID NO: 3 corresponds to a CD47 ligand, specifically, the SIRPα extracellular domain, fused to an Fc(ALIE) fragment (e.g., ¶ 0056, 0101). These limitations fail to satisfy the written description requirement because the claim language allows for variability in the coding sequences of the structural features (i.e., the anti-CD47 antibody or the SIRPα ECD) which are required for the function of binding to CD47, which in turn would be expected to unpredictably alter the final structure of the protein and affect its CD47-binding function.
State of the prior 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) that provide the majority of the contact residues for the binding of the antibody to its target epitope. See Almagro (Frontiers in Immunology (2018) 8: 1751), “The IgG Molecule” (page 3) and Figure 1. Sela-Culang (Frontiers in Immunology (2013) 4: 302) further teaches, “A major focus in analyzing the structural basis for [antigen] recognition has been in identifying the exact boundaries of the CDRs in a given [antibody]. It is a common practice to identify paratopes through the identification of CDRs” (page 3). Although the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. Ni (The Protein Journal (2024) 43: 683-696) teaches, “Mutations, even one mutation, introduced in the CDRs through [somatic hypermutation] can change the binding properties and repertoire of antibodies. However, how just one-point mutation can dramatically change the recognition profiles of the antibody is still unclear” (Introduction). Furthermore, while affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody, those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori (Almagro, pages 3 and 6-7).
Exemplary anti-CD47 antibodies, having a full complement of three VH CDRs and three VL CDRs, are well-known in the art. Consider, for example, the teachings of Liu (WO 2011/143624 A2; cited in IDS); Grosveld (WO 2021/032174 A1; cited in IDS); and Gardai (CN 111448213 A; cited in IDS).
Regarding SIRPα, Liu (Journal of Molecular Biology (2007) 365(3): 680-693) teaches that binding of SIRPα to CD47 via its extracellular IgV domain regulates essential leukocyte functions (e.g., Abstract). Liu discloses that key residues implicated in the binding of SIRPα to CD47 include Gln67, Ala/Val57, and Met102; mutation of either Gln67 or Ala/Val57 ablates the direct binding of SIRPα to CD47 (e.g., Abstract; Results).
Scope of species disclosed in original specification. Example 1 discloses that a human CD47 extracellular domain antigen comprising residues 1-139 was prepared and used to generate 25 positive antibody clones (page 20). Ten clones were selected from these 25 positive clones to construct full-length antibodies (pages 20-21). Table 1 summarizes the heavy chain and light chain CDR sequences for three exemplary antibodies, Hu004-65, Hu004-73, and Hu004-101 (pages 22-23):
Hu004-65 has three heavy chain CDRs comprising SEQ ID NOs: 17-19, respectively (VH of SEQ ID NO: 9), and three light chain CDRs comprising SEQ ID NOs: 11-13, respectively (VL of SEQ ID NO: 5);
Hu004-73 has three heavy chain CDRs comprising SEQ ID NOs: 17-19, respectively (VH of SEQ ID NO: 9), and three light chain CDRs comprising SEQ ID NOs: 14-16, respectively (VL of SEQ ID NO: 7); and
Hu004-101 has three heavy chain CDRs comprising SEQ ID NOs: 17-19, respectively (VH of SEQ ID NO: 9), and three light chain CDRs comprising SEQ ID NOs: 22-24, respectively (VL of SEQ ID NO: 25).
Examples 7-10 discloses the construction and use of αCD47-Fc(ALIE) variants comprising 100% sequence identity to the DNA sequence of SEQ ID NO: 1. Example 11 discloses that a SIRPα-Fc(ALIE) antibody having the sequence shown in SEQ ID NO: 3 or 4 was utilized in in vitro mediated killing experiments ovarian tumor and lung tumor cell lines. The disclosure does not recite which residue(s) in either of these constructs may be mutated, up to 10% relative to the parent sequence, while retaining the ability to bind CD47 or mediate tumor cell killing.
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. In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. As established above, the full complement of three heavy chain CDRs and three light chain CDRs in a conventional antibody is the minimum structure required for antigen-binding. Of the antibodies generated by Applicant, the three clones described above are the only clones whose antigen-binding structures are clearly defined in the specification to the extent sufficient to establish written description support for an antibody having specific binding to CD47. The skilled artisan would not be able to discern a structure/function correlation for the claimed anti-CD47 antibodies other than those comprising all six CDRs present together in Hu004-65, Hu004-73, or Hu004-101. Furthermore, the skilled artisan would be unable to discern from Applicant's disclosure which base pair(s) in the nucleotide sequences of SEQ ID NOs: 1 and 3, up to 10% variability relative to the parent sequences, may be mutated without interfering with the required function of binding to CD47 as claimed.
Conclusion. For all of the reasons presented above, one of skill in the art would not know which of the countless other anti-CD47 antibodies or SIRPα variants encompassed by the highly general structural requirements of the claims would also possess the required functional activity. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of antibodies or SIRPα variants as broadly claimed at the time the application was filed.
(2)
Claim 15 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The invention appears to employ novel biological materials, in particular a recombinant vaccinia virus Tian Tan strain named “rTV-αCD47-Fc(ALIE)”, deposited at China Center for Type Culture Collection (CCTCC) (address: Wuhan University, Wuhan, China) with the deposit accession number CCTCC NO: V202080. Since the biological materials are essential to the claimed invention, they must be obtainable by a repeatable method set forth in the specification or otherwise readily available to the public. If the biological materials are not so obtainable or available, the requirements of 35 U.S.C. § 112 may be satisfied by a deposit of the biological materials.
The specification does not disclose a repeatable process to obtain the biological materials and it is not apparent if the biological materials are readily available to the public. It is noted that Applicant has deposited the biological materials at the China Center for Type Culture Collection (CCTCC) on January 8, 2021 (e.g., ¶ 0078 of the specification), but there is no indication in the specification as to public availability. If the deposit is made under the Budapest Treaty, then an affidavit or declaration by Applicant, or a statement by an attorney of record over his or her signature and registration number, stating that the specific biological materials have been deposited under the Budapest Treaty and that the biological materials will be irrevocably and without restriction or condition released to the public upon the issuance of a patent, would satisfy the deposit requirement made herein. If the deposit has not been made under the Budapest Treaty, then in order to certify that the deposit meets the criteria set forth in 37 C.F.R. 1.801-1.809, Applicant may provide assurance of compliance by an affidavit or declaration, or by a statement by an attorney of record over his or her signature and registration number, showing that:
a. during the pendency of this application, access to the invention will be afforded to
the Commissioner upon request;
b. all restrictions upon availability to the public will be irrevocably removed upon
granting of the patent;
c. the deposit will be maintained in a public depository for a period of 30 years or 5
years after the last request or for the effective life of the patent, whichever is
longer;
d. a test of the viability of the biological material at the time of the deposit will be
made (see 37 C.F.R. 1.807); and
e. the deposit will be replaced if it should ever become inviable.
Applicant’s attention is directed to MPEP § 2400 in general, and specifically to § 2411.05, as well as to 37 C.F.R. 1.809(d), where it is set forth that the “specification shall contain the accession number for the deposit, the date of the deposit, the name and address of the depository, and a description of the deposited material sufficient to specifically identify it and to permit examination.” The specification should be amended to include this information. However, Applicant is cautioned to avoid the entry of new matter into the specification by adding any other information.
Applicant is advised that the address for the American Type Culture Collection (ATCC) should appear in the specification. The address is:
American Type Culture Collection
10801 University Boulevard,
Manassas, VA 20110-2209
United States of America
(3)
Claim 18 is 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 treating a tumor by administering the recombinant oncolytic virus according to claim 10, does not reasonably provide enablement for preventing a tumor by the same method. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The amount of guidance, direction, and exemplification disclosed in the specification, as filed, would not be sufficient to enable the skilled artisan to use the claimed invention at the time the application was filed without undue experimentation. MPEP § 2164.01 states: “The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).”
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, which have been outlined in the Federal Circuit decision of In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), include, but are not limited to, the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed. See also Ex parte Forman, 230 USPQ 546 (BPAI 1986).
Nature of the invention / Breadth of the claims. The nature of the claimed invention at issue is a method for preventing a tumor in a subject, comprising administering to said subject an effective amount of a recombinant oncolytic virus which is operably inserted with or comprises a gene coding sequence of an anti-CD47 antibody or a CD47 ligand as set forth in claim 18.
State of the prior art / Predictability of the prior art. Clinical trials aimed at proving preventative cancer activity by a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossibly long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded cancer prevention trials with cancer incidence as an endpoint in all but a select few malignancies with treatments such as tamoxifen and finasteride. See review by Lee (Nature Reviews Cancer (2011) 11: 211-218) at page 211; National Cancer Institute (Cancer Prevention Overview, (PDQ®)–Patient Version).
Debela (SAGE Open Medicine (2021) 9: 20503121211034366) teaches that treating cancer has been a highly complex process, but that some therapeutic strategies have shown promise in patients. Conventional treatment approaches known in the field include surgery, chemotherapy, and radiotherapy (Abstract; page 2). More recent efforts have focused on the use of stem cell therapy, targeted drug therapy (e.g., monoclonal antibodies or small molecule inhibitors), gene therapy, and others (e.g., Abstract; pages 2-5). Debela further teaches that some combinatorial treatment strategies have been found to have a synergistic effect (page 1).
Working examples / Guidance in the specification. Example 7 discloses that a pSC65 vector containing an αCD47-Fc(ALIE) gene of interest (corresponding to SEQ ID NO: 1) was inserted into a recombinant vaccinia virus (rTV) corresponding to wild-type vaccinia virus Tian Tan strain (pages 26-28). The working examples disclose that the rTV-αCD47-Fc(ALIE) group, particularly in combination with hrCD16T cells or NK cells, demonstrated a killing effect in liver cancer cells (e.g., Example 9; Figure 10) and in lung cancer cells (e.g., Example 10; Figure 11) in vitro. The working examples also disclose that Hu004-65-Fc(ALIE) loaded in a poxvirus vector had in vitro killing activity against selected ovarian cancer and lung cancer tumor cell lines (e.g., Example 12; Figure 13).
While these results suggest that the Applicant is enabled to treat a tumor using the claimed method, they do not provide enablement for preventing such a tumor. The specification lacks the critical elements necessary for illustrating a predictable response in a population of subjects for preventing cancer. Reasonable guidance with respect to preventing any disease relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to particular types of cancer. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of the diagnosis and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent.
Conclusion. Upon careful consideration of the factors used to determine whether undue experimentation is required, the amount of guidance, direction, and exemplification disclosed in the specification, as filed, is not deemed sufficient to have enable the skilled artisan to use the claimed invention at the time the application was filed to prevent a tumor without undue and/or unreasonable experimentation.
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.
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.
(1)
Claims 1-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu (WO 2011/143624 A1; cited in IDS).
Liu describes humanized or chimeric anti-CD47 monoclonal antibodies and uses thereof (e.g., Abstract). Regarding claims 1-3, Liu describes an exemplary anti-CD47 antibody “B6H12” comprising a heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 11 (e.g., claim 7; Figure 1; Example 1, ¶ 0080-00103), which shares 100% sequence identity to the anti-CD47 comprising instant SEQ ID NO: 9, inclusive of the heavy chain CDRs set forth in instant SEQ ID NOs: 17-19. Regarding claims 4-5, Liu sets forth that the antibodies of the invention may be a full-length chimeric or humanized antibody, e.g., having a human immunoglobulin constant region of any isotype (IgG1, IgG2, IgG3, or IgG4) (e.g., ¶ 0006-0008).
Regarding claims 6-8, Liu discloses host cells, vectors, and isolated nucleic acids encoding the antibodies of the invention as well as methods of preparing said antibodies by culturing the host cells encoding the antibody so that the nucleic acid is expressed and recovering the antibody from the culture (e.g., ¶ 0013).
(2)
Claims 10-11, 14, 16, and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cao (Advances in Cell and Gene Therapy (2021) 4(2): e99; published online July 3, 2020; cited in IDS).
Cao investigated whether engineered oncolytic viruses (OVs) could be used to redirect tumor-associated macrophages to tumor cells for therapeutic benefit (e.g., Abstract). Pertinent to claims 10-11 and 14, Cao “engineered an oncolytic vaccinia virus (VV) to disrupt the CD47/SIRPα interaction by expressing a chimeric molecule that consists of the ectodomain of SIRPα and the Fc domain of IgG4 (SIRPα-Fc-VV)” (Abstract). Regarding claim 16, Cao teaches that the SIRPα-Fc minigene was subcloned into the pCMS1 shuttle plasmid of the F17R late promoter (Methods). Cao discloses that double-deleted VVs expressing the SIRPα-Fc were generated by recombination of the pCMS1 shuttle plasmids into the TK locus of the VSC20 strain of Western Reserve VV (Methods). Regarding claim 18, Cao describes in vivo experiments in which the engineered OVs were injected into mice for the purpose of treating osteosarcoma tumors (e.g., Abstract; Methods).
(3)
Claims 10-11, 14, 16, and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Song (WO 2018/049261 A1).
Song describes oncolytic vaccinia viruses (VV) encoding an immune checkpoint modulator where expression of the immune checkpoint modulator is driven by a late promoter, as well as uses thereof in treating cancer (e.g., Abstract). Pertinent to claims 10-11 and 14, Song teaches oncolytic VVs in which the immune checkpoint modulator is an inhibitor of CD47, including embodiments in which the immune checkpoint modulator comprises a SIRPα extracellular domain fused to an Fc fragment (e.g., ¶ 0008-¶ 0016, 0062-0103). The oncolytic virus encoding the immune checkpoint modulator may be selected from vaccinia virus, Seneca Valley virus, adenovirus, and others (e.g., ¶ 0014).
Song further teaches a method of treating cancer (e.g., AIDS-related lymphoma) that comprises administering pharmaceutical compositions comprising the oncolytic VVs of the invention (e.g., ¶ 0026-0028, 0302-0303), anticipating claim 18. Song also teaches methods of preparation for the oncolytic VV constructs of the invention, which comprise inserting isolated nucleic acids encoding the SIRPα extracellular domain into a vector (e.g., oncolytic VV vector) (e.g., ¶ 0431-04448), pertinent to claim 16. The recombinant viruses can be transfected into human 143 TK- cells (e.g., ¶ 0436).
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.
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.
Claims 10, 13, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Song (WO 2018/049261 A1) as applied to claims 10-11, 14, 16, and 18 above, and further in view of Shani (US 2019/0315834 A1), Wyatt (Current Protocols in Protein Science (2017) 89: 5.13.1 – 5.13.18), and Chakrabarti (BioTechniques (1997) 23(6): 1094-1097).
The teachings of Song are recited in the 35 U.S.C. § 102 rejection above.
However, Song does not teach a SIRPα-Fc(ALIE) gene construct having the sequence shown in instant SEQ ID NO: 3, or that said construct is subcloned into a TK region of a vaccinia virus shuttle plasmid pSC65.
Shani describes SIRPα-CD70 fusion proteins having utility in the treatment of cancer (e.g., colon cancer) (e.g., Abstract; ¶ 0014-0046). Shani teaches that in specific embodiments the SIRPα nucleic acid sequence comprises SEQ ID NO: 11 (e.g., ¶ 0097-0105), which comprises the SIRPα-Fc(ALIE) gene shown in instant SEQ ID NO: 3, relevant to claims 13 and 17. Shani teaches that the SIRPα-CD70 fusion proteins of the invention retained binding activity for CD47 (e.g., Example 1).
Wyatt reviews protocols for generating recombinant vaccinia viruses. Pertinent to claim 17, Wyatt writes, “The foreign gene of interest is subcloned into a plasmid transfer vector (Fig. 5.13.1) or assembled as a PCR fragment so that it is flanked by DNA from the vaccinia virus genome for insertion into a non-essential site. This recombinant plasmid is then transfected into BS-C-1 or other cells that have been infected with vaccinia virus. Homologous recombination occurs between the vaccinia virus genome and homologous sequences (Fig. 5.13.1). The recombinant virus is obtained in a cell lysate, which is then subjected to several rounds of plaque purification using appropriate selection and/or screening protocols (see Basic Protocol 2)” (Basic Protocol 1, pages 5.13.1-5.13.2). Wyatt states that the gene of interest should be subcloned into the multiple cloning site (MCS) in pSC65 or another suitable vector and the plasmid should be isolated using standard procedures (step 1a at page 5.13.3).
Further regarding the pSC65 shuttle plasmid, Chakrabarti teaches that pSC65 “provides 8 unique restriction endonuclease sites and the lacZ gene, which may be used for positive identification of recombinant viruses and subsequently for identifying infected cells” (page 1097). Chakrabarti teaches that the pSC65 plasmid and others have been used by many laboratories to produce recombinant vaccinia viruses following standard protocols (page 1097). Chakrabarti teaches that synthetic E/L promoters, which are contained in plasmid transfer vectors like pSC65, are simple to genetically manipulate due to their 40-bp size (page 1096).
In view of these further teachings, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the recombinant VV generation methods taught by Song by substituting the SIRPα ECD-Fc fusion described by Song with the SIRPα-Fc fusion protein taught by Shani, and to carry out the steps set forth in the method of instant claim 17 to generate a recombinant oncolytic virus based on the further teachings of Wyatt and Chakrabarti. The skilled artisan would have been motivated to use the SIRPα-Fc construct described by Shani because it demonstrates binding to CD47 and has utility in the treatment of various cancers. There would have been a reasonable expectation of success because the SIRPα-Fc fusions described by Song and Shani are functional equivalents which would be recognized by one of ordinary skill in the art to be suitable for the same purpose. The skilled artisan would further have been motivated to use a pSC65 plasmid shuttle because it contains a lacZ gene enabling detection of recombinant viruses and identification of infected cells and a synthetic E/L promoter that is simple to genetically manipulate according to Chakrabarti. There would have been a reasonable expectation of success because those of ordinary skill in the art would have recognized the suitability of pSC65 as a plasmid when generating recombinant VVs based on the teachings of Wyatt and Chakrabarti.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-8, 10-11, 14, and 16-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-11, and 13 of co-pending Application No. 18/724,346 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention.
Regarding claims 1-3 and 5, co-pending claims 1-3 and 5 recite a bispecific anti-CD47/anti-CD3 T-cell engager (BiTE) comprising an anti-CD47 VH comprising the amino acid sequence of SEQ ID NO: 19 (which shares 100% sequence identity to instant SEQ ID NO: 9, and inclusive of the CDRs comprising instant SEQ ID NOs: 17-19) and an anti-CD47 VL comprising the amino acid sequence of SEQ ID NO: 24 (which shares 100% sequence identity to instant SEQ ID NO: 7, and inclusive of the CDRs comprising instant SEQ ID NOs: 14-16).
Regarding claims 6-7 and 10-11, co-pending claims 7-8 recite an expression framework comprising a coding sequence encoding the BiTE of co-pending claim 1 as well as a recombinant oncolytic virus operably inserted with said expression framework. Regarding claim 14, co-pending claim 9 recites that the viral backbone of the oncolytic virus is derived from modified or engineered vaccinia virus Tian Tan strain or others.
Regarding claims 16-17, co-pending claim 11 recites a method for preparing the recombinant oncolytic virus of co-pending claim 8 reciting similar synthesis, subcloning, and transfection steps as the method set forth in instant claim 17. The expression frameworks comprising the nucleotide sequences of SEQ ID NO: 35, 36, and 33 share 100% sequence identity to instant SEQ ID NOs: 8, 10, and 26, respectively. Regarding claim 8, the preparation method recites a host cell (a TK143 cell) comprising the vector encoding the anti-CD47 BiTE. Regarding claim 18, co-pending claim 13 recites a method of treating a tumor that comprises administering to a subject in need thereof the recombinant oncolytic virus of co-pending claim 8.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
Prosecution Insights