DETAILED ACTION
Election/Restrictions
Applicant’s election of Group I, Claims 1-11 without traverse in the reply filed on 8/12/2026 is acknowledged.
Claims 12-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/12/2026.
Claims 1-19 are pending and will be examined on the merits.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 11 is 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 11 recites the limitation " wherein the composition" in line 1. There is insufficient antecedent basis for this limitation in the claim or claim 1 from which it depends. It is also unclear whether it is the composition or the polypeptide comprised in the composition that has the recited sequences listed (SEQ ID NOs: 9-12). Appropriate correction is required.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-11 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. This is a written description rejection.
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.
The claims are drawn to a method of optimizing expression of a protein comprising designing a DNA coding sequence corresponding to the protein, cloning into a viral-based vector, transfecting said vector into a host and extracting the protein comprising a polypeptide with at least two domains, the first domain capable of binding to CD3 and a second domain capable of binding to a target cell. The claims are drawn to a binding polypeptide having 80% identity to SEQ ID Nos: 9-12, which read on alteration within the sequences that can affect antigen binding.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or 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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
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). But while this overall structure is shared amongst antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level. By the time the invention was made, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008 (cited on IDS filed 10/03/2023); 13:1619-33 (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Chimeric antibodies comprise the heavy and light chain variable regions of a rodent antibody linked to human constant regions and preserve the entirety of the VH and VL of the parent antibody. Id. at 1619-20. Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4. Almagro provides a detailed discussion regarding various methods of humanization, including rationale design approaches and empirical approaches based on random screening. Almagro, Sections 4 and 5.
Examples of antigen binding domains comprising only a VH (or less commonly, a VL) that in turn comprise only three CDRs certainly do exist in the literature, but those antibodies generally comprise unique structures such as CDR1 and CDR3’s that are elongated in length and that are often disulfide linked. E.g., De Genst et al., Dev Comp Immunol 2006; 30:187-98 (cited on IDS filed 10/03/2023). “Shuffling” of the VL (or less commonly the VH) had also been used to improve affinity of a parent antibody in certain instances. But the procedure generally required a "dominant" VH (i.e., a VH that is primarily responsible for antigen specificity). E.g., Yoshinaga et al., J. Biochem 2008; 143:593-601 (cited on IDS filed 10/03/2023).
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification fails to provide guidance on which 20% of SEQ ID NO: 9-12 or 20% of the variable regions SEQ ID NOs: 1-4 or 20% of SEQ ID NOs: 6-7 can be altered and still retain CD3 binding or cancer cell binding.
The specification does not describe what residues within the CDRs confer the binding activity claimed. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for binding polypeptides other than those comprising 100% of SEQ ID NOs: 9-12. Although it is possible to screen for binding polypeptides which can bind CD3 or a target cell, however the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.”
In view of the prior art teaching, mentioned above, that variations within the CDRs render antigen binding unpredictable, one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of variant binding polypeptides (80% identity to SEQ ID NOs) recited in the method of treatment of the instant claims. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera of compositions used in the method of treatment. Applicant is invited to amend the claims to have 100% identity to any recited SEQ ID Nos:.
Claim Rejections - 35 USC § 103
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 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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-5 and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Yankelevich et al. (Pediatric Blood Cancer 2012, 59(7):1198-1205, cited on IDS filed 10/03/2023) in view of Irving et al. (WO/2016/014974, cited on IDS filed 10/03/2023) and Dardevet et al. (Toxin March 2015, 7(4):1079-1101, cited on IDS filed 10/03/2023).
The claims are drawn to a method of optimizing expression of a protein comprising designing a DNA coding sequence corresponding to the protein, cloning into a viral-based vector, transfecting said vector into a host and extracting the protein comprising a polypeptide with at least two domains, the first domain capable of binding to CD3 and a second domain capable of binding to a target cell of neuroectodermal origin. The claims are further drawn to wherein the polypeptide comprises 80% identity to SEQ ID NO: 9.
Yankelevich et al. teach making a bispecific antibody anti-CD3 x anti-GD2 which can redirect activated T cells to target GD2-positive neuroblastomas and induce cytokine response upon binding to targets. Bispecific CD3 and GD2 antibodies, labeled as “3F8 BiAb”, were tested for its dual binding specific to GD2 expressed on cancer cell lines and CD3 expressed on activated T-cells. Yankelevich et al. teach “the ganglioside GD2 is an attractive target for immunotherapy of neuroectodermal tumors”. Yankelevich et al. does not teach a chlorotoxin second domain. This deficiency is made up for by Irving et al. and Dardevet et al.
Irving et al. teach methods of making an activatable anti-CD3 epsilon single chain variable antibody (see paragraph [00090]). Irving et al. further teaches wherein the CD3 antibody can be a single chain antibody or scAb and can bind CD3 epsilon mouse or rat, chimeric, humanized or fully human (see paragraph [00065]). Irving et al. teach a linking peptide having the sequence (GGGGS)N (see paragraph [00064]) can be used to link the CD3 antibody to other antibodies, agents, or moieties. Irving et al. teach expression vectors including plasmids, retroviruses, YACs, and EBV derived episomes used for transfection into host cells for protein production.
Dardevet et al. teach that chlorotoxin can selectively bind to glioma cells and can be used as a therapeutic target peptide.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make a composition comprising a CD3 binding polypeptide, a linker, and a cancer cell (neuroectodermal) binding polypeptide having instant SEQ ID NO: 9 based on the teachings of Yankelevich et al., Irving et al., and Dardevet et al. One of ordinary skill in the art would have been motivated to make a bispecific polypeptide capable of targeting CD3 and neuroectodermal cancer cells via chlorotoxin instead of anti-GD2 as an immunotherapeutic to neuroblastoma based on the teachings of Yankelevich et al. of successfully making T-cells to target neuroectodermal cancer cells and Dardevet et al. teaching successful targeting of neuroectodermal glioma cells using chlorotoxin. Furthermore, one of ordinary skill in the art could use the specific anti-CD3 antibody taught by Irving et al. to successfully target and activate T-cells. A composition comprising the CD3 binding polypeptide and linker of Irving et al., and the chlorotoxin of Dardevet et al. would result in a composition having instant SEQ ID NO: 9 for use as a more targeted therapeutic for neuroblastoma patients.
Conclusion
Claims 1-11 are rejected.
No Claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MEERA NATARAJAN whose telephone number is (571)270-3058. The examiner can normally be reached on M-F 9AM - 5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JULIE WU can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Meera Natarajan/Primary Examiner, Art Unit 1643
Prosecution Insights