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 .
Information Disclosure Statement
The information disclosure statement (IDS) filed 06/12/2024 has been considered and the references therein are of record.
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 1-3, 11-12, 21-24, 29-30, 32, 37, 39-40, 42-43, and 75-76 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 1-3, 11-12, 21-24, 29-30, 32, 37, 39-40, 42-43, and 75-76 are rejected for recitation of intended result/effect without conferring some structural, material, or manipulative difference on the scope of the claim. The claims recite or are dependent upon the functional language of an “IL-15 domain” and “CTLA-4 antigen binding domain” without specifying the specific structure required to perform the function of IL-15 activity and CTLA-4 antigen binding. While claims 4, 6, 8, 9, 13, 15, 17, 19-20, 26-27, and 31 further limit the rejected claims by specifying specific amino acid sequences, the rejected claims do not provide the necessary structure that must be present to perform the requisite function. Further, claims 2-3 recite that the IL-2 domain is active and the activity is increased by the IL-15Ra sushi domain without providing the required mechanism that increases activity, the required structure that confers the activity, or the actions and effects of the activity. The mechanism steps and requisite structure are merely implied by the functional language and thus the scope of the claim is undefined. Absent additional active method steps and structure, it is unclear how these claims further limit the scope of the parent claim. MPEP 2173.05(g) states: “the use of functional language in a claim may fail ‘to provide a clear-cut indication of the scope of the subject matter embraced by the claim' and thus be indefinite.” It further states: “Examiners should consider the following factors when examining claims that contain functional language to determine whether the language is ambiguous: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim.” The claims are rejected since they fail to meet all (3) criteria set forth in MPEP 2173.05(g).
The term “preferentially” in claims 21 & 30 is a relative term which renders the claims indefinite. The term “preferentially” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The phrase “preferentially” is not defined and renders the formation of a heterodimer as indefinite.
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 1-4, 6, 11-13, 15, 17, 19-24, 26-27, 29-32, 42-43, and 75 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 claims contain 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.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. The claims recite an IL-15 domain (claims 1, 23, 29, 32, 42, & 75), active IL-15 domain (claims 2-3), CTLA-4 antigen binding domain (claims 1, 32, 42), CTLA-4 antibody (claim 11), CTLA-4 antibody first heavy chain (claims 12, 21-22, 24, 29), CTLA-4 antibody second heavy chain (claims 12), CTLA-4 antibody first light chain (claim 29), CTLA-4 antibody second light chain (claim 29), recombinant fusion protein capable of treating disease or disorder (claim 42), and recombinant fusion protein capable of treating cancer (claim 43), each of which encompasses a genus of agents. Also, the claims 4, 6, 13, 15, 17, 19-20, 26-27 and 31 recite sequences having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NOs: 1-2, 9-14, and 16, each of which encompasses a genus of agents. These claims do not require that the genera of the claims possess any particular structure or other distinguishing feature that is characteristic of the genera as a whole. Therefore the claims are drawn to genera for which there is inadequate written description.
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 (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), 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 MPEP 2163(II)(3)(a)(i)(C).
In the instant case, the only identifying characteristic present in the claim is a recitation of requisite activity, such as IL-15 activity, capable of binding a CTLA-4 antigen, capable of treating disease/disorder and cancer, and forming a heterodimer. There is not even identification of any particular portion of a structure that must be conserved for said activity. Regarding the genera of the claims, the specification describes species in the working Examples that fall within the claimed genera (Specification pg. 82-93). From the specification, it is clear that Applicant is in possession of the species of an anti-CTLA-4-IL-15Ra-sushi-IL-15 fusion protein with 100% identity to SEQ ID NOs: 1-2, 9-14, and 16 used to treat a colon and lung cancer mouse model (Fig. 13). The claims, however, are not limited to those species but also includes the genera of an IL-15 domain (claims 1, 23, 29, 32, 42, & 75), active IL-15 domain (claims 2-3), CTLA-4 antigen binding domain (claims 1, 32, 42), CTLA-4 antibody (claim 11), CTLA-4 antibody first heavy chain (claims 12, 21-22, 24, 29), CTLA-4 antibody second heavy chain (claims 12), CTLA-4 antibody first light chain (claim 29), CTLA-4 antibody second light chain (claim 29), recombinant fusion protein capable of treating any disease or disorder (claim 42), recombinant fusion protein capable of treating any cancer (claim 43), and any sequences having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NOs: 1-2, 9-14 & 16, yet the specification fails to provide a representative number of species within the recited genera. Regarding the sequences with 80-99% identity to the instant sequences, the specification does not teach which residues of each sequence are critical for function and would have to be retained. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics of each genus as a whole, or representative number of species within each genus, the specification does not provide adequate written description of the claimed genera.
Claims 1-4, 6, 11-13, 15, 17, 19-24, 26-27, 29-32, 42-43, and 75 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 an anti-CTLA-4-IL-15Ra-sushi-IL-15 fusion protein with 100% identity to SEQ ID NOs: 1-2, 9-14, and 16 used to treat colon and lung cancer, does not reasonably provide enablement for the genera of IL-15 domain (claims 1, 23, 29, 32, 42, & 75), active IL-15 domain (claims 2-3), CTLA-4 antigen binding domain (claims 1, 32, 42), CTLA-4 antibody (claim 11), CTLA-4 antibody first heavy chain (claims 12, 21-22, 24, 29), CTLA-4 antibody second heavy chain (claims 12), CTLA-4 antibody first light chain (claim 29), CTLA-4 antibody second light chain (claim 29), recombinant fusion protein capable of treating any disease or disorder (claim 42), recombinant fusion protein capable of treating any cancer (claim 43), and any sequences having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NOs: 1-2, 9-14 & 16. 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.
In AMGEN INC. ET AL. v. SANOFI ET AL. (No. 21-757, decided May 18, 2023), the Supreme Court held that Amgen was not enabled for “the entire genus” of antibodies that (1) “bind to specific amino acid residues on PCSK9,” and (2) “block PCSK9 from binding to [LDL receptors]” (872 F. 3d 1367, 1372) even though Amgen identified the amino acid sequences of 26 antibodies that perform these two functions.
The case law applies to the instant claims which require multiple genera of recombinant fusion proteins containing antibody domains capable of treating any disease/disorder and cancer, yet the inventors have disclosed no amino acid sequences for any of the claimed genera and have only disclosed use of an anti-CTLA-4-IL-15Ra-sushi-IL-15 fusion protein with 100% identity to SEQ ID NOs: 1-2, 9-14, and 16 used to treat colon and lung cancer.
In Amgen, the Supreme Court has stated:
“An antibody' s structure does much to dictate its function—its ability to bind to an antigen and, in some instances, to block other molecules in the body from doing the same. ‘For an antibody to bind to an antigen, the two surfaces have to fit together and contact each other at multiple points.' Id., at 11. But just because an antibody can bind to an antigen does not mean that it can also block. To bind and block, the antibody must establish a sufficiently broad, strong, and stable bond to the antigen. See ibid. Different antibodies have different binding and blocking capacities based on the amino acids that compose them and their three-dimensional shapes. See id., at 11–12.
Despite recent advances, aspects of antibody science remain unpredictable. For example, scientists understand that changing even one amino acid in the sequence can alter an antibody' s structure and function. See id., at 14. But scientists cannot always accurately predict exactly how trading one amino acid for another will affect an antibody' s structure and function. Ibid.”
A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentec, Inc., V. Novo Nordisk, 42 USPQ 2d 100, (CAFC 1997), the court held that: "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" and that "[t]ossing out the mere germ of an idea does not constitute enabling disclosure". The court further stated that "when there is no disclosure of any specific starting material or of any of the conditions under which a process is to be carried out, undue experimentation is required; there is a failure to meet the enablement requirements that cannot be rectified by asserting that all of the disclosure related to the process is within the skill of the art","[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement". The instant specification is not enabling for the full scope of the claimed invention because one cannot follow the guidance presented therein and practice the claimed method without first making a substantial inventive contribution.
Given that structure is essential to function, and given the unpredictability within the art with respect to creating antibodies, a person having ordinary skill in the art would have to perform further experimentation in order to make and use the genera encompassed by the claims, commensurate in scope with the breadth of the claims. Given the nature of the invention, a skilled artisan would have to make many anti-CTLA-4-IL-15Ra-sushi-IL-15 fusion proteins, then use those in the method claimed of treating diseases/disorders and cancers in order to demonstrate making and using with a reasonable expectation of success. This amount of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the method for the breadth of what is claimed.
Thus, claims 1-4, 6, 11-13, 15, 17, 19-24, 26-27, 29-32, 42-43, and 75 lack enablement.
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 (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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 6, 8-9, 11-13, 15, 17, 19-27, 29-32, 37, 39-40, 42-43, and 75-76 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al., 2019 (WO2019246392A1) in view of Wong et al., 2018 (WO2018075989A1) (see IDS document).
Instant claims are towards a recombinant fusion protein comprising four polypeptides. The first polypeptide comprises, from N- to C-terminus, a first CTLA- 4 antibody heavy chain, an IL-15Ra sushi domain, and an IL-15 domain, wherein the IL-15 domain and IL-15Ra sushi domain are linked using a GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 15) linker. The second polypeptide is a second CTLA-4 heavy chain, which forms a heterodimer with the first heavy chain. The third and fourth polypeptides are CTLA-4 antibody light chains. The first polypeptide can contain alternate linkers (SEQ ID NO: 15 & 23-26). Also, the N-terminus of the IL-15Ra sushi domain can be linked to the C-terminus of the second heavy chain, instead of the first heavy chain. The CTLA-4 antibody heavy chains comprise complementarity determining region (CDR) sequences of SEQ ID NO: 5-7. The CTLA-4 antibody light chains comprise complementarity determining region (CDR) sequences of SEQ ID NO: 3-4. Further claims are drawn to a vector for the protein, a pharmaceutical composition for the protein that is suitable for parenteral administration, a method of making the protein, a method of treating a cancer patient by administering the protein, and a kit with the protein.
Li teaches a recombinant fusion protein comprising four polypeptides (para [0312]). One polypeptide comprises, from N- to C-terminus, a CTLA- 4 antibody heavy chain, an IL-15 domain, and IL-15Ra sushi domain, wherein the IL-15 domain and IL-15Ra sushi domain are linked using a linker (claims 24-25, SEQ ID NO: 130). The polypeptide can contain alternate linkers (para [0195-0200], Table 12). A second polypeptide is a second CTLA-4 heavy chain, which forms a heterodimer with the first heavy chain (para [0091], [0110], & [0143]). The third and fourth polypeptides are CTLA-4 antibody light chains (para [0105-0108] & [0138]). Further claims are drawn to the polynucleotide encoding the recombinant fusion protein (para [0200-0204]), a vector comprising a polynucleotide for the protein (claims 44-45), a pharmaceutical composition for the protein that is suitable for parenteral administration (claim 34), a method of making the protein (claims 46-47), and a method of treating a cancer patient by administering the protein (claims 35-36).
Li SEQ ID NO: 130 teaches a CTLA- 4 antibody heavy chain with 99.1% and 98.7% sequence identity to instant SEQ ID NO: 10 and 11, respectively, which encompasses instant SEQ ID NO: 5-7 & 12-14. The alignment data between Li SEQ ID NO: 130 and instant SEQ ID NO: 10 and 11 are shown below.
Li SEQ ID NO: 130 teaches an IL-15 domain with 99.1% sequence identity to instant SEQ ID NO: 1, which is shown below.
PNG
media_image5.png
185
592
media_image5.png
Greyscale
Li SEQ ID NO: 130 teaches an IL-15Ra sushi domain with 100% sequence identity to instant SEQ ID NO: 2, which is shown below.
PNG
media_image6.png
197
606
media_image6.png
Greyscale
Li SEQ ID NO: 114 teaches a linker with 100% sequence identity to instant SEQ ID NO: 15, which is shown below.
PNG
media_image7.png
115
604
media_image7.png
Greyscale
Li SEQ ID NO: 109 teaches a linker with 100% sequence identity to instant SEQ ID NO: 23, which is shown below.
PNG
media_image8.png
114
598
media_image8.png
Greyscale
Li SEQ ID NO: 118 teaches a linker with 100% sequence identity to instant SEQ ID NO: 24, which is shown below.
PNG
media_image9.png
123
595
media_image9.png
Greyscale
Li SEQ ID NO: 126 teaches a linker with 100% sequence identity to instant SEQ ID NO: 25, which is shown below.
PNG
media_image10.png
125
593
media_image10.png
Greyscale
Li SEQ ID NO: 127 teaches a linker with 100% sequence identity to instant SEQ ID NO: 26, which is shown below.
PNG
media_image11.png
119
594
media_image11.png
Greyscale
Li SEQ ID NO: 131 teaches a CTLA- 4 antibody light chain with 100% sequence identity to instant SEQ ID NO: 9, which encompasses the three CRD sequences, GAF and instant SEQ ID NO: 3-4. The alignment data between Li SEQ ID NO: 131 and instant SEQ ID NO: 9 is shown below.
PNG
media_image12.png
297
604
media_image12.png
Greyscale
Li does not explicitly teach the order of a fusion protein where the CTLA- 4 antibody heavy chain is connected to an IL-15Ra sushi domain and the L-15Ra sushi domain is connected to the IL-15 domain. Li does not explicitly teach a kit comprising a therapeutically effective amount of the recombinant fusion protein.
Wong teaches the order of a fusion protein where the CTLA- 4 antibody heavy chain is connected to an IL-15Ra sushi domain and the L-15Ra sushi domain is connected to the IL-15 domain (page 2). Wong teaches a kit comprising a therapeutically effective amount of the protein (page 41).
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosure of Li and Wong. One with ordinary skill in the art would be motivated to make and use the claimed invention by combining the sequences of Li into the order of the fusion protein’s domains as taught by Wong because both Li and Wong teach the fusion protein works effectively to treat cancer. Furthermore, an ordinary artisan would have found it obvious to combine the kit of Wong with the fusion protein of Li because Wong teaches the kits can be used for ameliorating disease. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references. Therefore, claims 1-4, 6, 8-9, 11-13, 15, 17, 19-27, 29-32, 37, 39-40, 42-43, & 75-76 are obvious in view of the disclosures of Li and Wong.
Conclusion
No claims are allowed.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH CESARE whose telephone number is (571)272-6908. The examiner can normally be reached Monday - Friday 10am-4pm.
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, Jeffrey Stucker can be reached at (571) 272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOSEPH D. CESARE/ Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675