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 .
Claims 1-8 and 10-11 are pending and will be examined on the merits.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Note: the embedded hyperlinks are on pages 14 and 22 of the Specification.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1-8 and 10-11 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.
Claims 1, 2, 3, 4 and 11
Regarding claims 1-4 and 11, each instance of the phrase "for example" as well as the parentheses surrounding the limitations preceded by “for example”, each independently render the respective claim indefinite because it is unclear whether the limitation(s) following the phrase and/or contained within the parentheses are part of the claimed invention. See MPEP § 2173.05(d).
Note: for examination purposes, all limitations contained within parentheses will be viewed as optional and non-limiting.
Claims 1, 3, 4, 5, 11
Regarding claims 1-5 and 11, each instance of the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Note: for examination, the limitations indicated as being “preferable” will be viewed as optional and non-limiting.
Claims 1-8 and 10-11 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. This is a written description rejection.
Scope of the claimed antibodies
Instant claims 1, 6-8 and 10-11
Instant claims 1, 6-8 and 10-11 are directed to antibodies capable of performing the recited function of specifically binding to B7-H3. Regarding the antibody structure required to perform this function, instant claim 1 recites that comprises: 1) a VH comprising one, two or three CDRs, selected from the group consisting of: a) HCDR1 is selected from SEQ ID NOs: 5 or 11, b) HCDR2 is selected from SEQ ID NOs: 6, 12, 24 or 26 and c) HCDR3 is selected from SEQ ID NOs: 7 and 13 and/or 2) a VL comprising one, two or three CDRs selected from the group consisting of: a) LCDR1 is selected from 8 or 14, b) LCDR2 is selected from SEQ ID NOs: 9, 15 and 25 and c) LCDR3 is SEQ ID NO: 10. Additionally, each LCDR and HCDR is permitted to be modified with “one or more amino acid substitutions, deletions or additions”, which is recited for each CDR in instant claim 1. Instant claim 1 provides no guidance or limitations on which amino acids may be substituted in place of which other amino acids and instant claim 1 provides no upper limit on the number of variant amino acids per CDR. As such, independent claim 1 as well as dependent claims 6-8 and 10-11 are directed any antibody comprising at least one CDR selected from any of the respective SEQ ID NOs, as well as variant CDRs encompassing all possible permutations of amino acids and that is capable of performing the recited function of specifically binding B7-H3. Therefore, in its broadest sense, the structural limitations of instant claim 1 encompass all antibodies capable of specifically binding B7-H3 in existence as well as all anti-B7-H3 antibodies that ever will exist because there are absolutely no restrictions on the number or identity of the variant amino acids present in the binding-critical CDR regions.
Claims 2-5
Claim 2 is directly dependent on claim 1 by specifying that the amino acid sequences of the HC CDRs and LC CDRs of the antibody of claim 1 are selected from one of four combinations of three LC CDRs and three HC CDRs, with each CDR being identified by SEQ ID NO. For example, option (i) of claim 2 is the combination of SEQ ID NOs 5, 6, 7, 8, 9 and 10. Additionally, each LCDR and HCDR is permitted to be modified with “one or more amino acid substitutions, deletions or additions”, which is recited for each CDR in instant claim 2. Neither instant claim 1 nor instant claim 2 provide no guidance or limitations on which amino acids may be substituted in place of which other amino acids and instant claim 2 provides no upper limit on the number of variant amino acids per CDR. As such, independent claim 2 as well as dependent claims 3-5 are directed any antibody comprising HC and LC CDRs having amino acid sequences selected from any of the combinations of CDR sequences recited in claim 2, as well as variant CDRs encompassing all possible permutations of amino acids and that is capable of performing the recited function of specifically binding B7-H3. Therefore, in its broadest sense, the structural limitations of instant claim 1 encompass all antibodies capable of specifically binding B7-H3 in existence as well as all anti-B7-H3 antibodies that ever will exist because there are absolutely no restrictions on the number or identity of the variant amino acids present in the binding-critical CDR regions.
Description of Claimed Antibodies in specification
The instant Specification a total of three antibodies capable of binding B7-H3 and comprising a distinct combination of three heavy chain CDRs paired with three light chain CDRs, which are disclosed in Table 4, which is found on pages 23-24 of the instant Specification. The disclosed antibodies capable of binding B7-H3 and their corresponding CDRs are:
antibody mAb152/mAb272, comprising HCDR 1, 2 and 3 of SEQ ID NOs: 5, 6 and 7, respectively as numbered as per Kabat and HCDR 1, 2 and 3 of SEQ ID NOs: 11, 12 and 13, respectively as numbered as per IMGT and LCDR 1, 2 and 3 of SEQ ID NOs: 8, 9 and 10, respectively as numbered as per Kabat and LCDR 1, 2 and 3 of SEQ ID NOs: 14, 15 and 10, respectively as numbered as per IMGT
Antibody AB125/AB123, comprising HCDR 1, 2 and 3 of SEQ ID NOs:5, 24 and 7, respectively as numbered as per Kabat and HCDR 1, 2 and 3 of SEQ ID NOs: 11, 26 and 13, respectively as numbered as per IMGT and LCDR 1, 2 and 3 of SEQ ID NOs: 8, 25 and 10, respectively as numbered as per Kabat and LCDR 1, 2 and 3 of SEQ ID NOs: 14, 15 and 10, respectively as numbered as per IMGT
Antibody AB127/AB128, comprising HCDR 1, 2 and 3 of SEQ ID NOs:5, 6 and 7, respectively as numbered as per Kabat and HCDR 1, 2 and 3 of SEQ ID NOs: 11, 12 and 13, respectively as numbered as per IMGT and LCDR 1, 2 and 3 of SEQ ID NOs: 8, 25 and 10, respectively as numbered as per Kabat and LCDR 1, 2 and 3 of SEQ ID NOs: 14, 15 and 10, respectively as numbered as per IMGT.
Additionally, antibodies mAb152 and mAb272 are murine antibodies and AB125, AB126, AB127 and AB128 are humanized (Specification, p 24, ¶ 1). The instant Specification also discloses that the VH sequences for mAb152, mAb272, AB125, AB126, AB127 and AB128 are SEQ ID NOs: 1, 3, 16, 18, 20 and 22, respectively and VL sequences for mAb152, mAb272, AB125, AB126, AB127 and AB128 are SEQ ID NOs: 2, 4, 17, 19, 21 and 23, respectively.
Instant claim 1 also contains pairings of CDRs not reflected in the disclosed antibodies. For example, an antibody comprising HCDR 1, 2 and 3 of SEQ ID NOs: 5, 26 and 7 and LCDR 1, 2 and 3 of SEQ ID NOs: 14, 25 and 10 is encompassed by instant claim 1, however the Specification does not disclose any antibodies with this CDR pairing capable of performing the required function of specifically binding B7-H3. Additionally, the instant Specification does not disclose any examples of variant antibodies comprising CDR sequences with “one or more amino acid substitutions, additions or deletions” to any of the numbered sequences capable of performing the required function of specifically binding B7-H3.
State of the Relevant Art
As was well-known in the antibody art, antibodies as a class share an overall structure generally comprising two heavy chain polypeptides that each comprises a heavy chain variable region (VH) and a heavy chain constant region made up of several domain (CH1, hinge, CH2, CH3, and for some antibodies, a CH4). Each of the heavy chains pairs with a light chain polypeptide that comprises a light chain variable region (VL) and a constant region. Sela-Culang (Sela-Culang, et al., Front in Immunol. 2013; Vol. 4; Article 302) teaches on the subject of the structural basis of antibody-antigen recognition (Sela-Culang, Abstract). Sela-Culang teaches that there is a lack of intrinsic properties linking epitopic vs non-epitopic residues based on features present in said residues suggests that epitopes depend, to a great extent, on the antibody that recognizes them (Sela-Culang, p 2, ¶ 7). Sela-Culang teaches that antibodies fold in such a manner such that six hypervariable loops of the light and heavy domains of an antibody (three loops on the HC and three on the LC) are folded together and form the antigen binding site (Sela-Culang, p 3, ¶ 2). Sela-Culang teaches that the complimentary determining regions (CDRs) are amino acid sequences within this hypervariable region and that amino acids that define the CDR regions are typically defined based on numbering schemes (e.g., Kabat, Chothia, IMGT) derived from empirical studies of the boundaries between the framework and binding residues of the antibodies (Sela-Culang), p 3, ¶ 3). Sela-Culang teaches that identification of paratopes (the portion of an antibody which binds an antigen) is done through the identification of CDRs but CDRs, as identified by methods such as Kabat, Chothia and IMGT may miss ~20% of antigen binding residues (Sela-Culang, 4, ¶ 1-2). Sela-Culang teaches that each CDR has its own unique amino acid composition (i.e., different from the other CDRs) and each CDR has a unique set of contact preferences (Sela-Culang, p 5, ¶ 1).
Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict what an antibody with a particular set of functional properties would look like structurally. As discussed above, neither an epitope nor a paratope can be calculated a priori based on properties of the component amino acids. Furthermore, each and every CDR sequence is unique and distinct and, as such, a CDR sequence cannot be predicted, either from the epitope sequence of from the CDR sequences of the antibody, if known.
In addition to the importance of the CDR regions, Sela-Culang also teaches that framework residues are also play an important role in antigen binding (Sela-Culang, P 7, ¶ 3). These framework residues can be divided into two types. The first are framework residues that actually contact the antigen and therefore are part of the binding site (Sela-Culang, p 7 ¶ 4). The second type of framework residues that affect antigen binding are framework residues that do not directly contact the antigen but affect binding indirectly (Sela-Culang, p 7, ¶ 5). Some of the framework residues are in close proximity to the CDR regions of the parental antibody, with these FR residues providing structural support that permits the CDRs to adopt the right conformation to form the antigen binding.
The other type of framework residues that indirectly affect antigen binding are further from the CDR regions and affect the relative orientation of the VH and VL regions, and thus the orientation of the CDRs relative to each other (Sela-Culang, p 7, ¶ 6). Sela-Culang also teaches that the effect of framework residues on antigen binding is impossible to predict a priori. For example, Sela-Culang teaches that positions in FR-3 of the heavy chain affects the orientation of CDRH1 relative to CDRH2, however this is not always the case, as it has been shown that mutating a Lys in this region for either a Val, Ala or Arg resulted in affinity differences but no structural changes (Sela-Culang, p 7, ¶ 5).
Additionally, at the time of filing, numerous anti-B7-H3 antibodies were known in the art DuBridge (DuBridge, et al., US 9,963,509 B2; Issued 5/8/2018; priority to 12/23/2014 via US 62/095,969) discloses numerous conventional anti-B7-H3 antibodies, all of which comprise six distinct CDRs (DuBridge, claims 1, 3, 5, 7, 9, 11 and 13).
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that a “representative number of species” means that the species that 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.
As stated and articulated above, instant claim 1 encompasses CDR pairings not reflected in the instant Specification. Instant claim 1 encompasses a total of 96 pairings of 3 heavy chain CDRs paired with 3 light chain CDRs:
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A disclosure of three distinct pairings of three HC CDRs with three LC CDRs is not reflective of the 96 pairings of numbered SEQ ID NOs encompassed by instant claim 1. Additionally, the disclosure of zero antibodies comprising “one or more amino acid substitutions, additions or deletions” to any of the numbered CDR sequences recited in claims 1 and 2 that is capable of performing the required function of specifically binding B7-H3 is not sufficient to be reflective of the genera of variant CDR sequences recited in clams 1 and 2. This is because each of instant claims 1 and 2 encompass an astronomically large number of antibodies which is literally uncountable because it comprises an unknown number of yet-identified anti-B7-H3 antibodies, all of which comprise “one or more amino acid substitutions, additions or deletions” to any of the numbered sequences
Identifying characteristics and structure/function correlation
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 noted above, the art generally accepted that the combination of the CDRs within the VH and VL pair of an antibody was the minimum structure essential for binding specificity and the framework residues also play a role in antigen binding and a disclosure of an antigen or epitope does not permit a skilled artisan to envision the structure an antibody would need to have to bind that antigen or epitope, even if the amino acid sequence of that epitope is known.
The teachings of Sela-Culang make very clear that a structure-function relationship between an antibody’s CDRs and the epitope it binds is not understood well enough to permit a skilled artisan to analyze an epitopic sequence and envision, a priori, the required CDR structure required to form a functional antibody capable of binding that epitope. Sela-Culang teaches that CDRs are independent structurally and each possess independent binding preferences. There is nothing in the present disclosure nor the prior art that would lead one of skill in the art to believe that the disclosure contains any new discoveries that would supplant these notions. The lack of known structure/function correlation between any given antibody’s VH and VL structure and that antibody’s ability to bind its respective antigen means that it is highly unlikely that a skilled artisan would be able to start with the CDR amino acid sequences of claims 1 and 2 and envision, a priori which, if any, of the variant CDR sequences of claims 1 or 2 are capable of forming a function antibody capable of performing the required function of binding B7H3.
Because the species disclosed are insufficient to be considered representative of either the unfathomably large number of possible variations to the binding-critical CDR regions, coupled with the lack of established structure/function correlation, the claims lack written description and Applicant was not in possession of the invention as claimed.
Claim 11 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 methods of treating a tumor, does not reasonably provide enablement for methods of preventing a tumor. 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 factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re wands, 858 F.2d 731, 737.8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The instant claims are drawn to a method of treatment and/or prevention of a tumor, said method comprising administering to said subject a composition comprising the anti-B7-H3 antibodies of instant claim 1.
When given the broadest reasonable interpretation, “a subject in need thereof” includes humans and non-experimental animals.
The Merriam-Webster definition of the word “prevent”—“to keep from happening or existing”. Thus, the broadest reasonable interpretation of the claim is that the method comprising the administration of the instant claimed composition comprising the anti-B7-H3 antibodies of instant claim 1 described in the preceding paragraph prophylactically prevents cancer from occurring by killing every cancer cell present or stopping every healthy cell from becoming cancerous.
The skilled artisan recognized that before any method of preventing a particular cancer could be practiced with any level of predictability, some method of identifying subjects predisposed to the particular cancer must be available. While the art has advanced in recent years, it is still highly unpredictable not only which individuals will develop a particular cancer, but also when a “preventative” therapy will be helpful.
Breast cancer illustrates the difficulties associated with detecting and preventing cancer. The skilled artisan generally recognized symptoms of breast cancer to include changes in the breast such as the presence of a lump, nipple discharge, or other changes in the shape or texture of the breast. However, such symptoms are non-specific and have multiple other potential causes. Even detection of a breast mass by mammography is only an early step in the diagnosis of breast cancer. As noted in a 2014 article in the World Journal of Clinical Oncology, following an abnormal mammographic finding exam, biopsy is required for a diagnosis (cancer vs. benign lesion) and staging is required to determine appropriate treatment (Shah, et al. World J Clin Oncol 2014 August 10; 5(3): 283-298, Table 1).
Further, even in individuals judged to have a twofold increased risk of developing breast cancer, prevention with tamoxifen was incomplete. Briefly, high risk women were given either tamoxifen or a placebo and the occurrence of breast cancer was monitored for 20 years. The placebo group had a breast cancer rate of 12.3% and the treatment group had a breast cancer rate of 7.8 %. (Cuzick, et al Lancet Oncol 2015 Jan; 16(1) 67-75, Results, page 4). While tamoxifen did reduce the risk of the occurrence of breast cancer, it did not completely prevent it. It should be noted that the Specification is not enabling for any method of preventing any type of cancer, said method comprising administering an antibody of claim 1.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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)(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.
Claim(s) 1-8 and 10-11 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Cheung (Cheung, et al., CA 2959356; Published 02/20/2024; Priority to 8/27/2014 via US 62/042,457).
Note on interpretation
The instant claims are directed to an antibody that binds to B7-H3 comprising the recited CDR sequences, wherein the sequences comprise one or more (including all the resides) are substitutions, additions or deletions. As such, any B7H3 antibody anticipates claims 1 and 2 because it is possible to start with any CDR sequence present in any given anti-B7H3 antibody, and arrive at the any of the instant claimed antibody by making “one or more substitutions, additions and/or deletions.
Regarding claims 1-2, Cheung discloses anti-B7H3 antibodies (Cheung, Abstract). Regarding instant claims 6 and 8, Cheung discloses that anti-B7H3 antibodies were prepared by a process consisting of: 1) obtaining plasmid pBluescript expression vector comprising anti-B7H3 sequences (meaning the genetic engineering was performed by someone at some point; also reads on claim 6 as this is a DNA molecule encoding an anti-B7H3 antibody)), 2) transfecting mammalian CHO-S cells with the expression vector, 3) culturing the cells in OptiCHO serum free medium (which produced anti-B7H3 antibodies) and 4) purifying the antibody with protein A affinity chromatography (Cheung, ¶ 00393). The anti-B7H3 antibody of Cheung is the same as instant claimed antibody that binds to B7H3 comprising CDR sequences of SEQ ID NOs:5-10, wherein ALL residues are modified. Regarding instant claim 7, Cheung discloses pharmaceutical compositions (Cheung, claim 17) comprising anti-B7H3 antibodies specific to B7H3 isoforms 2Ig-B7H3 or 4Ig-B7H3 (Cheung, claim 1). Regarding instant claim 10, Cheung discloses bispecific antibodies specific for B7H3 and CD3 (Cheung, ¶ 00310). Regarding instant claim 11, Cheung discloses methods of treating cancer comprising administering anti-B7H3 antibodies (Cheung, ¶ 0028).
Conclusion
Claims 1-8 and 10-11 are rejected.
The Specification is objected to.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sydney Van Druff whose telephone number is (571)272-2085. The examiner can normally be reached 10 am - 6 pm.
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/SYDNEY VAN DRUFF/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643
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