DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse and amendment filed May 4, 2026 is acknowledged. Claims 1-24, 27, 29-30, 33, and 36-129 have been cancelled. Claims 25-26, 28, 31-32 and 34-35 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022,
That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). See for example, Tables 11, 11a, 11b, 11c, Table 2, Table 4, and Table 5. Please review the specification for other sequences that are not identified. Correction is required.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Trademarks
The use of the term for example, Perkin Elmer (paragraph [6510) (which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Please, review the specification for other trademarks and make the appropriate corrections.
Claim Rejections - 35 USC § 112
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 25-26, 28, 31-32 and 34-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
The claims are drawn to a masked cytokine comprising: a cytokine moiety, a masking moiety, and an engineered Fc domain comprising a tumor-associated protease cleavage site; wherein the engineered Fc domain is fused to the cytokine moiety or the masking moiety such that the masking moiety binds to the cytokine moiety and upon cleavage of the tumor- associated protease cleavage site on the engineered Fc domain, the cytokine moiety is released from the masking moiety and a masked therapeutically active molecule comprising: a therapeutically active domain, a masking moiety, and an engineered Fc domain comprising a tumor-associated protease cleavage site; wherein the engineered Fc domain is fused to the therapeutically active domain or the masking moiety such that the masking moiety binds to the therapeutically active domain and upon cleavage of the tumor-associated protease cleavage site on the engineered Fc domain, the therapeutically active domain is released from the masking moiety.
First, the claims encompass a masked cytokine in which the specification defines it as the following. The specification discloses that the cleavable Fc domain is engineered to comprise at least one protease cleavage site. The engineered domain comprises one or more amino acid substitutions as compared to a wild-type Fc domain, wherein the substitutions create a protease cleavage site [paragraph 15]. The specification discloses the one or more amino acid substitutions are in the hinge region. In some embodiments, the one or more amino acid substitutions are in the CH3 domain and in some embodiments, the one or more amino acid substitutions are in the CH2-CH3 linker [paragraph 17]. The specification discloses that cytokine molecules is for example, IL-12 or a functional fragment thereof [paragraph 38]. The specification discloses that in some embodiments, the masking moiety is a receptor of the cytokine or variant thereof or fragment thereof [paragraph 40]. The specification teach a therapeutic molecule which may be an agent that has a therapeutic effect such as suppression of tumor growth, invasion and progression and in some embodiments, the therapeutic molecule is a cytokine, a variant thereof, or a functional fragment thereof [paragraph 11]. Thus, the masked cytokine molecule of the invention comprise cytokine moieties, cleavable FC domains, hinge regions, CH3 or CH2-CH3 domains and therapeutic molecules with any structure. Because the masked cytokines comprise the aforementioned components without any defined structure, there is no structure function correlation.
Therefore, the specification does not provide adequate written description to identify the broad and variable genus of antibody derivatives because, inter alia, the specification does not disclose a correlation between the necessary structure of the masked cytokines and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Accordingly, the specification does not define any structural features commonly possessed by members of the genus, because while the description of an ability of the claimed active fragments may generically describe the masked cytokine molecule’s function, it does not describe the masked cytokines itself. A definition by function does not suffice to define the genus because it is only an indication of what the masked cytokine molecule does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of agents is highly variable (i.e., each active fragment would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed active fragments have no correlation between their structure and function.
Furthermore, Applicant have not shown possession of a representative number of species that have the claimed function(s). While the specification clearly sets forth a correlation between the fully described masked cytokines, and the function(s), this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed masked cytokines and encompass a vast genus of molecules of varying biological genera. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Given the vast number of masked cytokine molecules that are encompassed by the claims, the disclosure of a few species is not sufficiently representative of the broad genus of masked cytokine molecules encompassed by the claims. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The encompassed molecules have no correlation between their structure and function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. 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.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
Second, the state of the art outlines challenges with regard to immunocytokine development and treatment. Shi et al (Advancements and challenges in immunocytokines: A new arsenal against cancer, Acta Pharmaceutica Sinica B, volume 14, issue 11, November 2024, pages 4649-4664) teach safety concerns remain substantial barriers to immunocytokines' development. To address this challenge, we explore potential strategies, such as cytokine engineering and prodrug design, which can foster next-generation immunocytokines development (see the Abstract). Shi et al teach initially recognized for its cytotoxic properties, TNF-a is now understood to also have an immunosuppressive function, promoting the accumulation and/or activity of Tregs, regulatory B lymphocytes (Bregs), as well as MDSCs98. This duality poses challenges for the future development of TNF-based immunocytokines (page 4659). Shi et al teach immunocytokines are hindered by the “cytokine sink” effect where they are trapped by cognate receptors in circulation before reaching their target tumor sites. Moreover, studies have reported that only a minimal portion of immunocytokine accumulates in neoplastic lesion (in the best cases, 0.01%‒0.1% injected dose/gram of tumor), leading to toxicity similar to the parental cytokine (page 4659). Shi et al teach that “How to “match” antibodies and cytokines requires careful consideration. An essential criterion is that immunocytokines should demonstrate superior antitumor activity and safety compared to the combined administration of antibodies and cytokines” (page 4660).
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the 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 Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
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.
Claim(s) 25-26, 28, 31-32, and 34-35 is/are rejected under 35 U.S.C.102 (a)(1) and 102(a)(2) as being anticipated by Karow et al (WO 2020/069398 A1 published April 2, 2020).
Claim 25 is drawn to a masked cytokine comprising: a cytokine moiety, a masking moiety, and an engineered Fc domain comprising a tumor-associated protease cleavage site; wherein the engineered Fc domain is fused to the cytokine moiety or the masking moiety such that the masking moiety binds to the cytokine moiety and upon cleavage of the tumor- associated protease cleavage site on the engineered Fc domain, the cytokine moiety is released from the masking moiety.
Claim 26 is drawn to the masked cytokine of claim 25, wherein the engineered Fc domain is fused to the cytokine moiety or the masking moiety via a non-cleavable linker.
Claim 27 is drawn to a masked therapeutically active molecule comprising: a therapeutically active domain, a masking moiety, and an engineered Fc domain comprising a tumor-associated protease cleavage site; wherein the engineered Fc domain is fused to the therapeutically active domain or the masking moiety such that the masking moiety binds to the therapeutically active domain and upon cleavage of the tumor-associated protease cleavage site on the engineered Fc domain, the therapeutically active domain is released from the masking moiety.
Claim 31 is drawn to the masked therapeutically active molecule of claim 28, wherein the therapeutically active domain is a cell engager, or a co-stimulatory domain.
Claims 32 is drawn to a masked cytokine comprising: a cytokine moiety, a masking moiety, and a carrier moiety comprising an engineered tumor-associated protease cleavage site; wherein the carrier moiety is fused to the cytokine moiety and/or the masking moiety such that the masking moiety binds to the cytokine moiety and upon cleavage of the engineered tumor- associated protease cleavage site, the cytokine moiety is activated.
Claim 34 is drawn to the masked cytokine of claim 32, wherein the carrier moiety is a half-life extension domain selected from albumin, transferrin, or a tissue factor.
Claim 35 is drawn to the masked cytokine of claim 32, wherein the carrier moiety is selected from immunoglobulin, Fab, scFv, VHH, nanobody, VH, VL, single-domain Ab immunoglobulin kappa constant region (CK) and immunoglobulin lambda constant region (CL).
Karow et al relate to the engineering and use of masked cytokines or functional fragments thereof that, in some embodiments, are engineered to be masked by a masking moiety at one or more receptor binding site(s) of the cytokine or functional fragment thereof. In some embodiments, the cytokines are engineered to be activatable by a protease at a target site, such as in a tumor microenvironment, by including a proteolytically cleavable linker. In some embodiments, the proteolytically cleavable linker links the cytokine to the masking moiety, links the cytokine to a half-life extension domain, and/or links the masking moiety to a half-life extension domain. The masking moiety blocks, occludes, inhibits (e.g., decreases) or otherwise prevents (e.g., masks) the activity or binding of the cytokine to its cognate receptor or protein. Upon proteolytic cleavage of the cleavable linker at the target site, the cytokine becomes activated, which renders it capable of binding to its cognate receptor or protein with increased affinity [paragraph 0007]. Karow et al teach in one embodiment, the half-life extension domain is conjugated to an immune stimulant, such as a stimulator of interferon genes (STING) agonist, such as a cyclic dinucleotide (CDN), such as cGAMP, c-di-AMP, c-di-GMP, cAIMP, c-di-IMP, or 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide or a toll-like receptor (TLR) agonist, such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, or TLR 10 (therapeutic domain). Karow et al that the first half-life extension domain and/or the second half-life extension domain of the linked first and second half-life extension domains is an Fc domain or fragment thereof (carrier moiety) [paragraph 311]. Karow et al teach in one embodiment, the antibody or fragment thereof is a Fragment crystallizable domain (Fc domain) or fragment thereof [page 0015]. Karow et al teach that the masked cytokine comprises a half-life extension domain that comprises an albumin peptide polypeptide or fragment or variant thereof [paragraph 0346]. Thus, Karow et al anticipate the claimed invention.
No claims are allowed.
Conclusion
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to VANESSA L. FORD whose telephone number is 571.272.0857. The examiner can normally be reached Monday – Friday, 8:00 am to 4:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford can be reached at (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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