Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 87-102 directed to a humanized antibody or antigen binding fragment thereof), Species A (an anti-B7H3 antibody having a VH, VL, HCDR1-3, LCDR1-3, HFR1-4, and LFR1-4 according to SEQ ID NOs: 6, 12, 94-96, 79-81, 44-47, and 40-43, respectively), and Species B (a SADA according to SEQ ID NO: 132) in the reply filed on September 30, 2025 is acknowledged.
Claims 103-104 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 30, 2025.
No prior art was found on the elected SEQ ID NO: 6, SEQ ID NO: 12, and SEQ ID NO: 132 which are part of Markush Groups recited in claims 92, 93 and 98, respectively. Pursuant to MPEP 803.02 III C. 2., searching and examination was expanded to encompass SEQ ID NOs: 2-5, 7-9, 11, 13-14, and 16-17.
Status of Claims
Claims 87-104 are currently pending. Claims 87-102 are under examination and claims 103-104 are withdrawn pursuant to 37 CFR 1.142(b) as above.
Claim Interpretation
Note well, SEQ ID NOs: 64-66 and 67-69, as recited in claim 89, are the same as the elected SEQ ID NOs: 94-96 and 79-81, respectively, thus claim 89 has been included with examined claims. All teachings of the art are cited with respect to SEQ ID NOs: 94-96 and 79-81, however it is to be understood that the same teachings also apply to the limitations of the CDRs according to claim 89.
Claim Objections
Claims 87, 88, 90, 91, 92, 93, and 94 are objected to because of the following informalities:
Claims 87, 88, 90, and 91 recite “CDR regions” or “FR regions.” The person of ordinary skill would understand “CDR” stands for “complementarity determining region” and “FR” stands for “framework region.” Therefore, “CDR regions” reads as “complementarity determining region regions” and “FR regions” reads as “framework region regions”. To avoid such redundancy and clarify the language of the claims, claim 87 in line 3 can be amended to read “complementarity determining regions (CDRs)”, followed in claim 88 simply by using the term “CDRs” in place of “CDR regions.” Similarly, line 5 of claim 87 can recite “framework regions (FRs)”, followed in claims 90 and 91 by simply using the term “FRs” in place of “FR regions.”
Claims 92 and 94 recite “a heavy chain variable region VH.” The person of ordinary skill in the art would understand that VH is an abbreviation of “heavy chain variable region.” As set forth, claim 92 thus reads “comprising a heavy chain variable region heavy chain variable region”. Claims 93 and 94 recite “light chain variable region VL,” which is similarly redundant. One of the following options is recommended:
Remove “heavy chain variable region” and “light chain variable region”;
Remove “VH” and “VL”; or
Amend to “heavy chain variable region (VH)” and “light chain variable region (VL)”.
Appropriate correction is required.
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.
Claims 87-102 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.
Claim 87 recites a B7H3-binding humanized antibody, comprising CDR sequences having a total of at least 90% identity to those listed and framework regions (FR regions) having a total of at least 70% identity to those listed. The listed sequences of the CDRs and FR regions have overlapping sequences as exemplified below. Amino acids shared by a FR region according to SEQ ID NO: 44 and a CDR according to SEQ ID NO: 94 are underlined.
[AltContent: textbox (SEQ ID NO: 44)][AltContent: textbox (SEQ ID NO: 94)]
[AltContent: rect][AltContent: arrow][AltContent: arrow][AltContent: rect]SEQ ID NO: 6
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQATGQGLEWMGWIFPGDGSTQYNEKFQGRVTMTTNTSISTAYMELSSLRSEDTAVYYCARQTTATWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
It would be unclear to the skilled artisan what the metes and bounds of a sequence designated as “FR” and “CDR” would be in view of the aforementioned overlap. For example, some skilled artisans would argue that an antibody having the FR SEQ ID NO: 44 and the CDR SEQ ID NO: 94 would have a VH comprising the sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYD as is set forth in SEQ ID NO: 6. However, other skilled artisans would argue that FR regions and CDRs are mutually exclusive regions of an antibody, thus the scope of an antibody comprising a FR region according to SEQ ID NO: 44 and an HCDR1 according to SEQ ID NO: 94 would have a VH comprising the sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYTFTNYD. Therefore, the metes and bound of the claimed antibody according to claim 87 are indefinite.
The scope of claim 87 is further unclear because different skilled artisan would arrive at different interpretations of the required number of CDRs and framework regions selected from those sequence listed. For example, some skilled artisan would argue that an anti-B7H3 antibody of claim 87 requires all 6 CDRs to be cumulatively 90% identical to 6 CDR sequences selected from SEQ ID NOs: 25-30 and 64-99 and all 8 framework regions cumulatively 70% identical to 8 framework regions selected from SEQ ID NOs: 40-63, 108-131, 133 and 134. However, other skilled artisan would argue that since the number of CDRs and framework regions of those listed is not particularly claimed, claim 87 only requires, at most, 2 CDRs cumulatively 90% identical to 2 CDR sequences selected from SEQ ID NOs: 25-30 and 64-99 and at most 2 framework regions cumulatively 70% identical to 2 framework regions selected from SEQ ID NOs: 40-63, 108-131, 133 and 134. Therefore, claim 87 is indefinite for failing to particularly point out the metes and bounds of the claimed invention.
Note well, claims 90 and 91 are indefinite on the same grounds, as it is unclear whether the anti-B7H3 requires all of SEQ ID NOs: 40-47, or whether “FR regions selected from the group consisting of” (claim 90) and “heavy/light chain FR regions of” requires as few as two FR regions from SEQ ID NOs: 40-47.
Claims 88-89, and 95-102 are rejected by virtue of their dependency.
For searching and examination, claims 87, 90 and 91 are interpreted as having at least two CDRs and FR regions relating to the recited SEQ ID NOs.
Claim 92 is indefinite because it claims a heavy chain variable region selected from SEQ ID NOs: 2-9. However, SEQ ID NOs: 2-9 are full heavy chains. The metes and bounds of the antibody according to claim 92 are unclear because some skilled artisans may interpret the claim as requiring all limitations of a heavy chain set forth in a sequence selected from SEQ ID NOs: 2-9. Other skilled artisan would argue that claim 92 is limited an antibody comprising a heavy chain variable region of a full heavy chain sequence selected from SEQ ID NOs: 2-9.
Claim 93 is indefinite because it claims a light chain variable region selected from SEQ ID NOs: 11-14. However, SEQ ID NOs: 11-14 are full light chains. The metes and bounds of the antibody according to claim 93 are unclear because some skilled artisans may interpret the claim as requiring all limitations of a light chain set forth in a sequence selected from SEQ ID NOs: 11-14. Other skilled artisan would argue that claim 93 is limited an antibody comprising a light chain variable region of a full light chain sequence selected from SEQ ID NOs: 2-9.
For the purpose of applying art, claims 92 and 93 are interpreted as requiring at minimum the variable domain of a listed heavy / light chain SEQ ID NO, and not the full heavy / light chain sequence.
Claim 94 is indefinite because it recites “a” heavy chain variable region of SEQ ID NO: 6 and “a” light chain variable region of SEQ ID NO: 12. Some skilled artisan would interpret “a” as indicating that SEQ ID NO: 6 / 12 comprises multiple heavy / light chain variable regions from which the claimed VH / VL is selected. Other skilled artisan would interpret the scope of claim 94 as an antibody with “the” heavy chain variable region of SEQ ID NO: 6 and “the” light chain variable region of SEQ ID NO: 12.
The latter interpretation is adopted for the sake of searching and examination.
Claims 96 and 97 recite a bispecific and/or trispecific binding antibody. The metes and bounds of an antibody that is both bispecific and trispecific is indefinite. The person of ordinary skill in the art would interpret a “bispecific” antibody as binding to two different epitopes whereas a “trispecific” antibody binds to three different epitopes. It would be unclear to the skilled artisan how an antibody can both bind to only two and at the same time bind to as many as three epitopes.
For the purpose of searching and examination, claims 96 and 97 are interpreted with the scope of a “bispecific or trispecific” antibody.
The metes and bounds of claims 95 and 98 are indefinite because different skilled artisan may arrive at multiple different interpretations. Claim 98 depends from claim 97 which describes a SADA polypeptide linked to an antibody or antigen binding fragment of claim 87; wherein the antibody or antigen binding fragment is bispecific or trispecific and comprises an anti-B7H3 binding domain of claim 87 and a DOTA binding domain. Some skilled artisan would understand said SADA polypeptide as being an independent structure of the antibody or antigen binding fragment because the SADA polypeptide is claimed as being linked to and not comprising the antibody or antigen binding fragment. Claim 98 recites that the SADA polypeptide comprises SEQ ID NO: 16, 17, and 132. As an example, SEQ ID NO: 132 comprises an anti-B7H3, an anti-DOTA binding region, and a multimerization domain. Some skilled artisans would interpret the scope of claim 98 as a SADA polypeptide comprising, e.g. SEQ ID NO: 132, and further linked to an antibody or antigen binding fragment of claim 87; wherein the antibody or antigen binding fragment to which SEQ ID NO: 132 is linked, is bispecific or trispecific and comprises an anti-B7H3 binding domain of claim 87 and a DOTA binding domain. Other skilled artisan would argue that the scope of claim 98 does not require additional structure beyond the limitations of, e.g. SEQ ID NO: 132.
For the purpose of searching and examination, the limitations of claim 95 are interpreted as commensurate with the scope of “said polypeptide comprises an antibody or antigen binding fragment.” In other words, claim 98 is interpreted as not requiring additional structural elements beyond the elected species of SEQ ID NO: 132.
Claims 96 and 97 are rejected by virtue of their dependency on claim 95.
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 87-88, 90-93, and 95-102 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.
Claim 87 describes a genus of antibodies that bind to B7H3 comprising at least 90% identity to VH CDRs and VL CDRs. Pursuant to the interpretation set forth in Claim Rejections under 35 U.S.C. § 112(b) above, claims 87 and 88 are interpreted as having at least two of the listed sequences with a total of at least 90% identity (claim 87) or a total of 100% identity (claim 88). Leaving 4 CDRs undefined encompasses a tremendous amount of variation. For example, if HCDR1, HCDR2, LCDR1, and LCDR2 were left undefined according to the CDR boundaries indicated by the elected species, and assuming only proteinogenic amino acids are used, then the total number of structure encompassed by the claims is 2024. This is larger than the estimated number of stars in the entire universe (NASA retrieved November 25, 2025 from the Internet at <URL: https://universe.nasa.gov/stars/basics/>). Even if the claims were limited to, e.g. requiring a total of at least 90% identity to 6 CDRs that were defined according to one listed sequence per CDR, the scope would still allow for up to 4 amino changes in any CDR residue. As a representation of the amount of variability, this includes replacing an entire half of HCDR1 or 2, or 2/3 of LCDR1. Therefore, claims 87 and 88 encompass a massive amount of variation within the genus of antigen binding proteins that specifically bind to B7H3.
Claims 92 and 93 limit the variation of the genus to having a specifically defined VH or VL region. However, the pairing variable region may still have any sequence of CDRs. Claims 92 and 93, therefore, still describe a remarkable breadth of variation.
MPEP § 2163 states:
"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 ... reduction to drawings ... or 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. In unpredictable arts a widely variant genus cannot be represented by only one species. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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. Furthermore, establishment of a ‘reasonable structure-function correlation’ can also describe a genus and may be established ‘by the inventor as described in the specification,’ or ‘known in the art at the time of the filling date.’ See MPEP 2163 (II)(A)(3)(a)(ii) and Abb Vie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that ‘only describe[d] one type of structurally similar antibodies’ that ‘are not representative of the full variety or scope of the genus.’)."
Applicant discloses 8 humanized heavy chains (pgs. 28-30) and 4 humanized light chains (pgs. 30-31). Six of the heavy chains were paired with the four light chains to generate 24 structures having a binding affinity between about 1 x 10-8 to 9 x 10-9 (Example 2 and Table 1 on pg. 25 spanning pg. 26). However, all disclosed antibodies share the same CDRs. The art also teaches a number of humanized anti-B7H3 sharing CDR commonality with the claimed anti-B7H3 antibodies. For example, Cheung (WO 2016/033,225) teaches 7 humanized light chains and 6 humanized heavy chains. Again, these antibodies have the same CDRs as those disclosed in the specification, except for one variation have a single amino acid change in each of the HCDR2 and HCDR3 region, shown below.
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Therefore, the disclosed antibodies and those of the art are not representative of the full scope of the variation present in this claimed genus because they do not account for the variation to the claimed scope of CDR sequences. “[W]hen there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.” (see MPEP citation supra). Thus, one of ordinary skill in the art would not be able to reasonably say that the Applicant possessed a representative number of species that reflects the variation of the claimed genus.
The factual inquiry now turns upon whether there is a correlation between structural and functional characteristics. Since all but one unique set of CDR sequences are the same, there is no description of a structure-function correlation for the vast majority of CDR combinations represented by the instant claim.
"A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.)
The art is highly unpredictable in respect to correlations between the structure and binding properties of CDRs.
Rudikoff et al. found that a single amino acid change in a CDR completely altered antigen-binding specificity (Rudikoff et al. Proc Natl Acad Sci 1982. 79: 1979-1983; cited herewith, pg. 1982, left column, second full paragraph). Bedouelle et al. (FEES J. 2006 Jan;273(1):34-46; cited herewith) examined the effects of alanine substitutions on each of the residues of the antibody heavy and light chain CDR3 regions and showed mutation of certain residues cause a > 100 fold drop in the “off rate” for ligand dissociation (Bedouelle et al., pg. 38-39; see Table 2). Bedouelle suggests that some mutations had a direct effect on antigen binding while others indirectly affect the conformation of the antigen binding site, thereby indirectly affecting antigen binding (see Discussion Section). This illustrates the unpredictability of making mutations within the CDRs of an antibody, especially the CDR3 domains. Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28; cited herewith) teaches that antigen binding is resultant from the 6 CDRs, or hypervariable regions, the variable region of an antibody (see, page 416, column bridging paragraph, emphasis added). Vajdos used a shotgun scanning mutagenesis using phage displayed libraries of protein mutants, which required extensive experimentation to comprehensively scan the potential CDR sequence space (see page 416, right column, 2nd paragraph and pages 425-427, Materials and Methods). Furthermore, even after performing this comprehensive scanning mutagenesis of all CDR residues from the particular anti-ErB2 antibody, Vajdos would still not have been able to say which CDR residues were actually involved in antigen binding, and which were involved in stabilizing the secondary and tertiary structure of the CDRs within the context of the heavy and light chains as a whole, without the structure of the unbound antigen-binding site of the antibody to aid in their analysis (see, in particular, Discussion, pages 422- 425). Rather, Vajdos needed to perform not only a comprehensive shotgun scanning mutagenesis of all CDR residues of the antibody under study, but also needed a structure of the unbound antigen binding site in hand to gain a sufficient understanding of the contribution of each CDR to antigen-binding to adequately predict which CDR residues can be changed, and to what extent, or in what context of additional compensatory mutations in other regions of the antibody.
Collectively, Rudikoff et al. Bedouelle et al., and Vajdos et al. demonstrate the amino acids of a CDR that are responsible for binding with a particular antigen cannot be determined by observation of the amino acid sequence alone. Indeed, Vajdos et al. showed it required the epitope of the antigen as well. Additionally, the ability to bind to a particular antigen is extremely sensitive to changes in CDR sequences.
In conclusion, there are no representative species in the art and the species disclosed in the specification are not sufficient to represent the full breadth of the claimed invention according to instant claims 87 and 88. Furthermore, a structure-function correlation is not shown in the specification or the art to account for the high degree of variability of the CDRs as laid forth in the instant claims. While the Applicant has reduced a single combination of CDRs within the scope of the instantly claimed genus, there is not a sufficient written description of the antibodies according to instant claims 87 and 88. Thus claims 87 and 88 are rejected under of 35 U.S.C. 112(a) for failing to comply with the written description requirement. Claims 90-93 and 95-102 are additionally rejected by virtue of their dependency on claim 87. Note well, claim 98 is rejected insofar as it may be interpreted as further requiring an additional anti-B7H3 binding site according to claim 87 (see Claim Rejections under 35 U.S.C. § 112(b) above).
Claim 87-93, and 95-102 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.
As stated in MPEP §2164.01 (a), "there are many factors to consider when determining
whether there is sufficient evidence to support a determination that a disclosure does not satisfy
the enablement requirement and whether any experimentation is 'undue'." These factors include,
but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary to make or use the invention based on the
disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
Regarding the breadth and nature of the invention, please see pgs. 9 of this Office Action
above for a description of the scope of anti-B7H3 antibodies.
The amount of guidance or direction needed to enable the invention is inversely related to
the amount of knowledge in the state of the art as well as the predictability in the art. In re
Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The state of art indicates that antigen specificity is extremely sensitive to changes in as little as one amino acid in a CDR (see discussion on Rudikoff et al., Bedouelle et al., and Vajdos above). The specification does not provide directions on how to make and use the invention of antibodies that bind to B7H3 with any of the CDRs as set forth in instant claim 87 or 88 besides a single set of CDRs, i.e. those of the murine parent 8H9. Moreover, making changes to the binding region has been shown to yield highly unpredictable results in terms of binding specificity. Vajdos et al. teaches that an antibody moiety’s essential structural components for binding to a cognate antigen cannot be derived from the observation of the antibody’s binding region (i.e. VH, VL, and/or CDRs) alone, the cognate antigen must also be present. This would turn the process of determining which combinations of amino acids in the CDRs result in the property of binding B7H3 toward a rote trial and error experimentation. Since the claims encompass innumerable possible variations on account of having up to 4 CDRs with any sequence or up to 4 amino acid changes as set forth in instant claim 87 and 88, an undue amount of experimentation would be need to make the full scope of B7H3 antibodies as claimed.
“As long as the specification discloses at least one method for making and using the
claimed invention that bears a reasonable correlation to the entire scope of the claim, then the
enablement requirement of 35 U.S.C. 112 is satisfied. In re Fisher, 427 F.2d 833, 839, 166
USPQ 18, 24 (CCPA 1970)” (see MPEP 2164.01(b)).
Specification pg. 25 describes conventional methods well known in the art for humanization that were employed to generate the antibody species disclosed including. However, the specification does not provide direction as to which amino acids may be replaced while retaining the property of binding B7H3. The only direction provided is to graft the CDRs into human framework regions. As is evidenced by what is known in the art, there is no way to know which amino acid changes would result in improved binding affinity without testing each antibody individually, thus the skilled artisan would have had to practice undue experimentation to determine which amino acids could be changed while retaining B7H3 binding. Therefore, the specification does not provide sufficient instruction to make the full breadth of the B7H3 antibodies beyond trial and error experimentation. The generation of humanized variants having the same CDRs does not bear a reasonable correlation to the entire scope of the claimed invention which encompasses innumerable variations of the antigen binding domain on the basis of a level of high variability of the CDRs.
MPEP 2164.01 states:
“[t]he standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Minerals Separation Ltd. 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).”
Application of the Wands factors as discussed reveals that there is not enough support in the specification or the art to make the full scope of the B7H3 antibodies without an unreasonable amount of experimentation because of the unpredictable and laborious process of identifying which amino acid changes result in the claimed function of binding to B7H3. Therefore, upon contemplation of In re Fisher and the Wands factors, claims 87 and 88 have been found to lack enablement. Claims 90-93 and 95-102 are additionally rejected by virtue of their dependency on claim 87. Note well, claim 98 is rejected only insofar as it may be interpreted as further requiring an additional anti-B7H3 binding site according to claim 87 (see Claim Rejections under 35 U.S.C. § 112(b) above).
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 87-90 and 99-102 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Cheung in WO 2016/033225 A2 published March 3, 2016.
Cheung teaches a humanized version of the murine anti-B7H3 antibody 8H9 according to SEQ ID NO: 10 and SEQ ID NO: 2 (pg. 56 and pg. 57 and claim 5). Cheung’s humanized anti-B7H3 teaches CDR sequences instant SEQ ID NO: 79-81 with 100% identity and two FRs, instant SEQ ID NO: 43 and 47 with 100% identity, teaching the limitations of instant claims 87, 88, 89, and 90.
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Cheung, in claim 66, teaches a DNA or RNA encoding said anti-B7H3 antibody as in instant claims 99 and 100. On pg. 82 in ¶ [00354], Cheung teaches “[t]he nucleic acids described herein [i.e. including the nucleic acids of claim 66] can be cloned into any one or the many expression vectors… then transfected into cells of choice” as in instant claim 101. Cheung, in claim 42 teaches a pharmaceutical composition comprising the ant-B7H3 antibody, anticipating instant claim 102.
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.
Claims 87-90, 95-97, and 99-102 are rejected under 35 U.S.C. 103 as being unpatentable over Cheung in WO 2016/033225 A2 published March 3, 2016; as applied to claims 87-88, 90 and 99-102 above and further in view of Santich in WO 2018/204873 A1 published on November 8, 2018.
See discussion on Cheung as applied to claims 87-90 and 99-102 above. Cheung teaches that the anti-B7H3 is useful for treating B7H3 positive tumor cells (see ¶[0029] on pg. 4). In ¶ [208] on pg. 52, Cheung teaches that B7H3 is widely expressed on many solid tumors including prostate cancer, renal cell carcinoma, urothelial cell carcinoma, ovarian cancer, and more.
While Cheung teaches an anti-B7H3 antibody, Cheung does not teach said antibody is bispecific for DOTA and linked to a SADA polypeptide.
However, Santich teaches a self-assembly disassembly polypeptide (SADA) conjugated to a binding domain (see Abstract). SADA domains “can be designed and/or tailored to achieve environmentally-dependent multimerization with beneficial kinetic, thermodynamic, and/or pharmacologic properties… [such as] effective delivery of a payload to a target site… while minimizing risk of off-target interactions.” (¶ [002] on pg. 1). On pg. 6 in ¶ [0020], Santich directs the skilled artisan to include a first and/or second antibody component to direct the construct to a cell target. In the brief list of potential antigen targets, Santich includes anti-B7H3. Id. Santich also discloses a bispecific DOTA-engaging SADA conjugate (see ¶ [0033] on pg. 9). Radiolabeled DOTA-engaging SADA conjugates are useful for targeting therapeutic doses of radioactivity to tumors, while the dissociation kinetics combined with a tumor-specific antigen binding domain reduces off-target toxicity (see Example 7).
It would have been prima facie obvious to use Cheung’s anti-B7H3 as the antigen binding portion of Santich’s SADA constructs. The person of ordinary skill in the art would have been motivated to do so because Santich directs the skilled artisan to conjugate an anti-B7H3 binding domain to the SADA constructs. In doing so, one would have looked to art, particularly clinically relevant humanized anti-B7H3 antibodies and found Cheung’s disclosed humanized B7H3 antibodies as suitable for the SADA constructs of Santich. See citation of Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) in MPEP 2144.07. Particularly, Santich teaches that complete tumor eradication is achieved with targeted bispecific DOTA-engaging SADA conjugates (Example 7), and Cheung teaches that anti-B7H3 is useful for treating B7H3 positive cancers, which would have motivated the skilled artisans to treat B7H3 positive cancers with a conjugate comprising the SADA and DOTA-binding domains of Santich and the anti-B7H3 binding domain of Cheung. Moreover, Santich expresses the advantages of adding a SADA domain with an anti-B7H3 antibody, e.g. tailored multimerization, and the expectation of an advantages is the strongest rationale to combine references. See MPEP 2144 II. The skilled artisan would have had a reasonable expectation of success in Cheung’s anti-B7H3 antibody as an antibody conjugated to Santich’s SADA constructs in view of the level of skill in the art, explicit teachings and directions of Cheung and Santich, as well as the experimental evidence provided by each reference. Therefore, It would have been prima facie obvious to use Cheung’s anti-B7H3 as the antigen binding portion of Santich’s SADA constructs and in doing so one would have arrived at the SADA polypeptides of instant claim 95-97.
Claims 87-90, and 99-102 are rejected under 35 U.S.C. 103 as being obvious over Sequeira et al. in US 2023/0293738 effectively filed on April 24, 2020 in view of Cheung in WO 2016/033225 A2 published March 3, 2016.
The applied reference (Sequeira) has a common assignee (Y-mAbs Therapeutics Inc.) and inventor (Ahmed Mahiuddin and Sonia Sequeira) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Sequeira teaches a generic B7H3 binding antibody conjugated to a chelator in claim 66. Sequeira specifies in ¶ [0009] on pg. 1 that an anti-B7H3 clone, in one embodiment is 8H9 and the chelator is DOTA.
While Sequeira teaches a generic B7H3 binding antibody conjugated to a chelator in claim 66, Sequeira does not teach a humanized B7H3 antibody, nucleic acids, or cells.
Cheung teaches a humanized version of the murine anti-B7H3 antibody 8H9 according to SEQ ID NO: 10 and SEQ ID NO: 2 (pg. 56 and pg. 57 and claim 5). Cheung’s humanized anti-B7H3 teaches CDR sequences instant SEQ ID NO: 79-81 with 100% identity and two FRs, instant SEQ ID NO: 43 and 47 with 100% identity, teaching the limitations of instant claims 87, 88, 89 and 90.
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Cheung, in claim 66, teaches a DNA or RNA encoding said anti-B7H3 antibody as in instant claims 99 and 100. On pg. 82 in ¶ [00354], Cheung teaches “[t]he nucleic acids described herein [i.e. including the nucleic acids of claim 66] can be cloned into any one or the many expression vectors… then transfected into cells of choice” as in instant claim 101. Cheung, in claim 42 teaches a pharmaceutical composition comprising the ant-B7H3 antibody, as in instant claim 102.
It would have been prima facie obvious to use Cheung’s anti-B7H3 antibody as the anti-B7H3 antibody of Sequeira. “The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” See MPEP 2144.07. In the instant case, the art recognized that Cheung’s antibody binds B7H3. The skilled artisan would have been motivated to use Cheung’s antibody for its intended purpose to bind B7H3 in the process of making the construct taught by Sequeira. Insofar as one may argue that one of skill would not have been motivated to select Cheung’s anti-B7H3 over the B7H3 binding domain taught by Sequeira, consider MPEP 2144.06 II on substituting equivalents known for the same purpose:
“[T]here was evidence that both phthalocyanine and selenium were known photoconductors in the art of electrophotography. ‘This, in our view, presents strong evidence of obviousness in substituting one for the other in an electrophotographic environment as a photoconductor.’ 209 USPQ at 759.” Smith v. Hayashi, 209 USPQ 754 (Bd. of Pat. Inter. 1980). “An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” MPEP 2144.06 II. Even if there was no express teachings explicitly directing the skilled artisan to choose Cheung’s anti-B7H3 over the anti-B7H3 of Sequeira, it would have been obvious to the skilled artisan to substitute Cheung’s anti-B7H3 because the art recognized that Cheung’s anti-B7H3 and Sequeira’s anti-B7H3 served the same purpose. That said, Cheung explicitly teaches a humanized version of 8H9, to which the sequences of Sequeira pertains, and the skilled artisan would have recognized the advantage of using a humanized antibody to treat human subjects. Thus, the skilled artisan would have been motivated by the expectation of an advantage in using Cheung’s humanized anti-B7H3 over Sequeira’s anti-B7H3. In view of the level of skill in the art and explicit teachings, the skilled artisan would have had a reasonable expectation of success in doing so. Therefore, it would have been prima facie obvious to use Cheung’s anti-B7H3 antibody as the anti-B7H3 antibody of Sequeira’s antibody-chelator construct.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claims 87-90, 95-97 and 99-102 are rejected under 35 U.S.C. 103 as being obvious over Sequeira et al. in US 2023/0293738 effectively filed on April 24, 2020 in view of Cheung in WO 2016/033225 A2 published March 3, 2016; as applied to claims 87-90, and 99-102 above and further in view of Santich in WO 2018/204873 A1 published on November 8, 2018.
The applied reference (Sequeira) has a common assignee (Y-mAbs Therapeutics Inc.) and inventor (Ahmed Mahiuddin and Sonia Sequeira) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
See discussion on Sequeira in view of Cheung as applied to claims 87, 88, 90, and 99-102 above. Sequeira claim 80 teaches treating cancer with the anti-B7H3-chelator conjugate. In claim 70, Sequeira teaches that the chelator is DOTA.
While Sequeira in view of Cheung teaches an anti-B7H3 antibody conjugated to DOTA, Sequeira in view of Cheung does not teach said antibody is bispecific for DOTA and linked to a SADA polypeptide.
However, Santich teaches a self-assembly disassembly polypeptide (SADA) conjugated to a binding domain (see Abstract). SADA domains “can be designed and/or tailored to achieve environmentally-dependent multimerization with beneficial kinetic, thermodynamic, and/or pharmacologic properties… [such as] effective delivery of a payload to a target site… while minimizing risk of off-target interactions.” (¶ [002] on pg. 1). On pg. 6 in ¶ [0020], Santich directs the skilled artisan to include a first and/or second antibody component to direct the construct to a cell target. In the brief list of potential antigen targets, Santich includes anti-B7H3. Id. Santich also discloses a bispecific DOTA-engaging SADA conjugate (see ¶ [0033] on pg. 9). Radiolabeled DOTA-engaging SADA conjugates are useful for targeting therapeutic doses of radioactivity to tumors, while the dissociation kinetics combined with a tumor-specific antigen binding domain reduces off-target toxicity (see Example 7).
It would have been prima facie obvious to use Sequeira in view of Cheung’s anti-B7H3 as the antigen binding portion of Santich’s SADA constructs. The person of ordinary skill in the art would have been motivated to do so because Santich directs the skilled artisan to conjugate an anti-B7H3 binding domain to the SADA constructs and teaches said constructs are bispecific for DOTA and a tumor target. Thus, Santich teaches toward the anti-B7H3-DOTA conjugate of Sequeira in view of Cheung, and Sequeira in view of Cheung teaches toward Santich’s bispecific DOTA constructs. Particularly, Santich teaches that complete tumor eradication is achieved with targeted bispecific DOTA-engaging SADA conjugates (Example 7), and Sequeira in view of Cheung teaches that anti-B7H3-DOTA conjugate is useful for treating cancers, which would have motivated the skilled artisans to treat B7H3 positive cancers with a conjugate comprising the SADA and DOTA-binding domains of Santich and the anti-B7H3 binding domain of Sequeira in view of Cheung. Moreover, Santich expresses the advantages of adding a SADA domain with an anti-B7H3 antibody, e.g. tailored multimerization, and the expectation of an advantages is the strongest rationale to combine references. See MPEP 2144 II. The skilled artisan would have had a reasonable expectation of success in Sequeira in view of Cheung’s anti-B7H3 antibody as an antibody conjugated to Santich’s SADA constructs in view of the level of skill in the art, explicit teachings and directions of Sequeira in view of Cheung and Santich, as well as the experimental evidence provided by each Santich. Therefore, it would have been prima facie obvious to use Sequeira in view of Cheung’s humanized anti-B7H3 as the antigen binding portion of Santich’s SADA constructs and in doing so one would have arrived at the SADA polypeptides of instant claim 95-97.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
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.
Claim 87-90 and 99-102 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 66-85 of copending Application No. 17/917,377 in view of Cheung in WO 2016/033225 A2 published March 3, 2016.
While ‘377 teaches a generic B7H3 binding antibody conjugated to a chelator in claim 66, ‘377 does not teach a humanized B7H3 antibody, nucleic acids, or cells.
Cheung teaches a humanized version of the murine anti-B7H3 antibody 8H9 according to SEQ ID NO: 10 and SEQ ID NO: 2 (pg. 56 and pg. 57 and claim 5). Cheung’s humanized anti-B7H3 teaches CDR sequences instant SEQ ID NO: 79-81 with 100% identity and two FRs, instant SEQ ID NO: 43 and 47 with 100% identity, teaching the limitations of instant claims 87, 88, 89 and 90.
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Cheung, in claim 66, teaches a DNA or RNA encoding said anti-B7H3 antibody as in instant claims 99 and 100. On pg. 82 in ¶ [00354], Cheung teaches “[t]he nucleic acids described herein [i.e. including the nucleic acids of claim 66] can be cloned into any one or the many expression vectors… then transfected into cells of choice” as in instant claim 101. Cheung, in claim 42 teaches a pharmaceutical composition comprising the ant-B7H3 antibody, as in instant claim 102.
It would have been prima facie obvious to use Cheung’s anti-B7H3 antibody as the anti-B7H3 antibody of ‘377. “The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” See MPEP 2144.07. In the instant case, the art recognized that Cheung’s antibody binds B7H3. The skilled artisan would have been motivated to use Cheung’s antibody for its intended purpose to bind B7H3 in the process of making the construct taught by ‘377. Insofar as one may argue that one of skill would not have been motivated to select Cheung’s anti-B7H3 over the B7H3 binding domain taught by ‘377, consider MPEP 2144.06 II