DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2 Applicant's amendment, filed on 4/11/2024, is acknowledged.
3. Claims 1, 23, 49, 61, 62, 67-69, 83, 88, 94, 98, 102, 105-107, 112, 118, 123 and 125 are pending.
4. Applicant’s IDS, filed 06/30/2025, is acknowledged.
5. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
6. Claims 1, 23, 49, 62, 67-69, 83, 88, 94, 98, 102, 105-107, 112, 118, 123 and 125 are rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
(i) The parenthesis “(…)” in claims 1, 23, 49, 61, 69, 83, 88, 94, 98, 102, 118 and 123, is indefinite because it is unclear whether the recited elements between the parenthesis are essential elements of the claim or not. It is not clear whether the sequences in the parenthesis ( ) are part of the claim and therefore, claimed; or not part of the claim and therefore, not claimed.
(ii) The recitation “comprises a scFv” in claim 62 is ambiguous because claim 62 depends from claim 61 which recites both conventional antibodies and single domain antibody (VHH), it is not clear how the VHH is now scFv.
(iii) the recitation “antibody” in claims 1, 23, 49, 61, 69, 83, 88, 94, 98, 102, 118 and 123 is ambiguous because the claims recite both conventional antibodies ((i)-(iii) and (viii)), and single-domain antibody (i.e., VHH) ((iv)-(vii), (ix) and (x)) while the definition of “antibody in the specification at [0107] does not included single-domain antibody.
(iv) the recitation “a heavy chain variable domain or region” in claims 1, 23, 49 (i-vi), 61, 69, 83, 88, 94, 98, 102, 118 and 123 ((iv)-(vii), (ix) and (x)) is indefinite because according to the specification these claimed CDRs were derived form single-domain antibody (VHH) not conventional antibody comprising a heavy chain variable domain or region.
(v) the recitation “an antibody domain” is indefinite because the recited structure in the claim is a single domain antibody not “an antibody domain”. The specification [0110] defined the term “antibody domain” to include either the VH or the VL.
7. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(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.
8. Claims 1, 23, 49, 62, 67-69, 83, 88, 94, 98, 102, 105-107, 112, 118, 123 and 125 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 23, 49, 61, 69, 83, 88, 94, 98, 102, 118 and 123 encompass a broad genus of antibodies comprising up to 3 amino acids modifications in each and every CDR as well as lacking target antigen specificity and lack framework regions for the antibody.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of treating cancer and binding CD276 polypeptide. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear 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, 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 genus.
The specification at [0350] discloses three Fab antibody fragments (Clones: #1, #2, and #3; FIGS. 2-4) and four VH domains (Clones: #4, #5, #6, and #7; FIGS. 5-8) were identified. In another panning, the amino acid sequence of SEQ ID NO:471 (a fragment of a human CD276 polypeptide containing a C2 domain) was fused to a 6×HIS tag for panning of a human Fab domain phage-displayed library. One Fab antibody fragment (Clone #8; FIG. 18) was identified. In another panning, another human VH domain phage-displayed library was used to pan against the same CD276 polypeptide. Two additional VH domains (Clones #9 and #10; FIGS. 26 and 27) were identified.
Clones #1 and #4-#7 also competed with Omburtamab (8H9) for binding to CD276 expressed by Du145 and PC3 cells, demonstrating that they can bind to CD276 present on cells and prevent the interaction of an anti-CD276 antibody with CD276 present on cells. Clones #2 and #3 did not compete with Omburtamab for binding to CD276 present on these cells, but they did bind to the CD276 expressing Du145 and PC3 cells. Clone #8 competed with DS-5573a (a full-sized anti-human CD276 afucosylated humanized antibody (150 kDa); Daiichi Sankyo) for binding to CD276 expressed on cells, demonstrating that it can bind to CD276 present on cells and prevent the interaction of an anti-CD276 antibody with CD276 present on cells. Clones #1-#7 did not compete with DS-5573a for binding to CD276 present on cells [0351].
[0352] Clones #9 and #10, two VH binders, bound to a CD276 polypeptide with EC50 values of 8.1 and 1.2 nM, respectively. Clone #9 and #10 exhibited aggregation resistance as tested by dynamic light scattering.
[0353] The heavy and light chains of the Fab's of Clones #1-3 were used to create scFv's,
Table 43 of the specification list the claimed 10 clones (conventional and sdAb) including the CDRs, VH/VHH and VL.
Claims 1, 23, 49, 61, 69, 83, 88, 94, 98, 102, 118 and 123 encompass a broad genus of antibodies comprising up to 3 amino acids modifications in each and every CDR as well as lacking target antigen specificity and lack framework regions for the antibody.
These claims, given its broadest reasonable interpretation consistent with the instant specification, reads on the genus of antibodies comprising a VH CDR1-3 and VL-CDR1-3 regions of SEQ ID NOs:X recited in the claims respectively, in the context of any non- specified framework and further paired with any non-specified VL/VH. The claims fail to cite that the antibody is capable of antigen binding site. The claims do not specify the antigen to which the claimed antibody binds. While the CDR are important for binding and contribute the majority of contact residues with the target antigen, the antigen specificity, i.e., CD276 is essential for identifying the other VL/VH missing framework. Accordingly, the skilled in the art would not be able to screen for any binding in the absence of antigen specificity to screen for the missing VL/VH frameworks in the claims.
The specification provides three anti-CD276 antibody, clones #1-#10/Ab1-Ab10, which were not random combinations of VH and VL i.e., they had specific VH domain paired with specific VL domain. The specification discloses 10 species within the instant claim scope. The instant application encompasses (but does not exemplify) CDRs modification up to 3 amino acids (deletion/addition/substitution) to the claimed HCDRs and LCDRs of each and every SEQ ID NOs: X. There is no teaching identifying what amino acids can be varied within the VH-CDRs and/or VL-CDRs antibody regions and still retain antibody or fragments capable of binding CD276. Brown et al (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region. Vajdos et al. (J. Mol. Biol. 2002, Jul 5, 320(2):415-28 at 416) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. The scope of the claims encompasses antibodies with VH or VL that encompass variation (addition, deletion, substitution) in their CDRs. The prior art discloses that 6 CDRs as being essential structure of antibody's binding site, and thus when intact, would provide enough structure to define the antibody's binding site (structure/function correlation) e.g., where amino acid substitutions can be made so as to change (e.g. 6CDR's) or retain (e.g., constant or variable framework) antigen binding. Neither the prior art nor applicant's disclosure defines sufficient representative antibodies and/or sufficient structure/function correlation between modifying the VLCDRs or VHCDRs regions of the disclosed antibody and the retention of a specific binding antibody that binds the CD276 to satisfy the WD requirement for the claims.
Regarding the amino acid substations in variable region, one skilled in the art have recognized challenge and trade-offs once it is applied in antibody. Rabia et al (Biochem Eng J. 2018 September 15; 137: 365-374) states that optimize antibody properties (affinity, specificity, stability, solubility and effector functions) with amino acid substitutions is challenge and is always trade-offs and states that an outstanding challenge in the field is that optimizing properties such as antibody affinity can lead to defects in other properties such as antibody stability, specificity and solubility. The resulting trade-offs between improvements in some antibody properties and reductions in others highlight that they are often interdependent and cannot be easily separated (introduction). Rabia et al further state given that the maximal chemical diversity of antibody CDRs is unimaginably large (>1078 antibody variants based on 20 different amino acids at ~60 sites in the CDRs), it is extremely challenging to define the sequence determinants of antibody specificity (para 2).
Brown et al (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region.
With respect to the recitation an antibody which does not comprise all 6 CDRs of the antibody that is produced by clones #1-#10, the Examiner directs Applicant's attention to the training material given by Bennett Celsa, Example 2: (Ab genus: modified CDR's) slides 34-40. Example 2 of the Training material ((https://www.aipla.org/docs/default-source/committee-documents/bcp-files/2020/uspto-bcp-antibody-slides-final.pdf?sfvrsn=b377f2cc_0) which requires that the claims explicitly recite the binding antigen in addition to all 6 CDR regions for fulfillment of the written description requirements under § 112, 1. Slide 39 indicates that a claim encompasses antibodies with 6 intact CDRs as well as a subgenus of antibodies that encompass up to 10% variation (fragments and/or analogs) in the 6 CDRs lacks written description. Slide 40 provide the conclusion that, a single antibody species would not be deemed by one of skill in the art to be representative of a claim that defines an antibody that binds antigen X comprising at least 90% homology to the 6 CDR of the VH and VL chains.
The facts of AbbVie parallel the claimed invention and provide significant guidance on the inherent unpredictability of protein engineering and the effect of amino acid substitutions on protein function. Abbvie is similar to the Federal Circuit's discussion in Novozymes A/S et al. v. Dupont Nutrition Biosciences APS et al., 2013 WL 3779376, Case No. 2012-1433, C.A.Fed; in both, the Federal Circuit emphasized the unpredictability in the art associated with changes in a parent enzyme or protein that can be effected at one or more positions in the sequence by amino acid addition, deletion, or substitution with at least nineteen other possibilities, e.g. counting natural amino acid residues. The basis of the unpredictability is rooted in the same principles that make improvements rare, namely that numerous subtle differences between amino acid residues determine protein binding and function. Because the subtle energetic contributions of each of these interactions is extraordinarily difficult to precisely quantify, and because the number of these interactions is so high even for a single protein-protein interface, innumerable small inaccuracies are amplified into unpredictability. This unpredictability is axiomatic in the field of protein engineering.
For example, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 ("[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology."); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation. Instead, AbbVie used a trial and error approach to modify individual amino acids in order to improve the IL-12 binding affinity. Moreover, the '128 and '485 patents of AbbVie do not describe any common structural features of the claimed antibodies. The asserted claims attempt to claim every fully human IL-12 antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity, and cover an antibody as different as Stelara, whereas the patents do not describe representative examples to support the full scope of the claims.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
9. Claims 107, 112, 123 and 125 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a mammal having a CD276 expressing cancer, wherein said method comprises administering, to said mammal, a composition of claim 98 or claim 102 with/out checkpoint inhibitor, does not reasonably provide enablement for treating each and every cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The specification disclosure does not enable one skilled in the art to practice the invention without an undue amount of experimentation.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The specification under example 3 design BiTE’s from binders having the ability to bind to a huma CD276 polypetideThe isolated BiTE's were tested in a killing assay that included target cells and T cells as effector cells. Briefly, 10,000 target cells (CHO-K1-CD276-Luci) were incubated with serially diluted BiTE's (BiTE #1, BiTE #2, BiTE #3, BiTE #5, or Control BiTE), followed by the addition of activated human T cells (E:T=20:1) per well in 96 well plates for 24 hours. A maximum protease activity control was used where 2 µL of 10% Triton X-100 per 100 µL was added to target cell only wells for 10-15 minutes before collecting the samples. Extracellular activity of dead-cell protease was detected using the Bio-Gloᵀ Luciferase Assay System (Promega G7941) or CytoTox-Gloᵀ Cytotoxicity Assay kit (Promega G9290) following the manufacturer's instructions. The percent cytotoxicity was calculated using the following formula: % Lysis = 100
(Experimental signal - Medium Background)/(Maximum signal - Medium Background).
CHO-K1-CD276-Luci. cell lysis was observed for T cells incubated in the presence of BiTE #1, BiTE #2, or BiTE #3, but not Control BiTE (Figure 25A). BiTE #2 also was tested using Du145 cancer cells and PC3 cancer cells as target cells. In both cases, cell lysis was observed for T cells incubated in the presence of BiTE #2, but not Control BiTE (Figures 25B and 25C). Likewise, Du145 cancer cell lysis was observed for T cells incubated in the presence of BiTE #5 (Figure 25D).
These results demonstrate that cell engagers (e.g., BiTEs) having the ability to bind to CD276 polypeptides can be designed using the CDRs and/or binders provided herein.
The instant claims are drawn to a large genus of methods which have not been developed yet to the point where a specific benefit exists in currently available form.
The scope of the claims encompasses the treatment of each and every cancer.
Besides in vitro result on the Du145 cancer cells an d PC3 cancer cells, no effect of any therapy was administered to each and every each and every cancer, each and every neuroinflammatory disease or disorder, each and every neurodegenerative disease or disorder, or any combination thereof with D2517 antibody.
The claims are directed to treating each and every cancer with the claimed product. However, it is not clear on the basis of in vitro studies, how to reliably predict in vivo relevance of adhesion pathways. Furthermore, even when in vivo studies have been performed, the resultant data are inconsistent. One major reason for the perplexing inconsistencies in this filed is that currently available animal models are not good predictors of human disease.
The specification does not provide exemplification of animal model to treat each and every each and every cancer with CD276 antibody.
One cannot extrapolate the teachings of the specification to the scope of the claims because the claims are drawn to the treatment of mammals having each and every cancer using the anti-CD276 antibody.
Given the relatively incomplete understanding in correlating between the CD276 antibody and in vivo animal models to clinical treatment each and every cancer involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims, the claims are not enabled.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
10. No claim is allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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August 11, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
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