DETAILED ACTION
Notice of AIA Status
The instant application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the Leahy-Smith America Invents Act (AIA ).
If the status of the application as subject to AIA or pre-AIA is incorrect, any correction of the statutory basis (e.g., changing from AIA to pre-AIA ) for a rejection under 35 U.S.C. §§ 102 and/or 103 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.
Status of the Claims
The listing of claims filed 9 June 2023 has been examined.
Claims 1–9, 14, 18, 19, 39–47, 52, 56, 76, 77, 81, and 86 are pending.
Claims 10–13, 15–17, 20–38, 48–51, 53–55, 57–75, 78–80, 82–85, and 87–114 are canceled.
Claims 3–6, 8, 9, 14, 18, 41–44, 46, 47, 52, 56, 77, 81*, and 86 are amended.
*Claim 81 has an incorrect status identifier. Appropriate correction is required.
Benefit of Earlier Filing Date
The instant application was filed 9 June 2023; is a national stage application of PCT/US2021/062953, filed 10 December 2021, and claims the benefit of U.S. Prov. Pat. App. Serial No. 63/123,983, filed 10 December 2020. Acknowledgment is made of Applicant’s claim.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 5 June 2024 and 18 October 2024 are acknowledged and have been considered.
Claim Interpretation
Claims recite “endoxifen residue,” “immunomodulatory drug (IMiD) residue,” and/or “thalidomide residue.”
The specification states: “A ‘residue’ of a molecule refers to the entire molecule but for the functional group used for conjugation to a linker . . .” (Spec., 38:4–7) (page:lines).
The definition in the specification will be applied to the terms in the claim.
Claim Rejections - 35 U.S.C. § 112
The following is a quotation 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.
Claims 1–7, 18, 19, 39–45, and 56 are rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement.
The claims contain subject matter that was not described in the specification in such a way as to reasonably convey to one of ordinary skill in the art that Applicant, at the time the application was filed, had possession of the claimed invention.
In Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc), the Federal Circuit stated “the hallmark of written description is disclosure.” A specification adequately describes an invention when it “reasonably conveys to those skilled in the art the inventor had possession of the claimed subject matter as of the filing date.” (Id.). “A ‘mere wish or plan’ for obtaining the claimed invention is not adequate written description.” Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1348 (Fed. Cir. 2011).
What is required to meet the written description requirement “varies with the nature and scope of the invention at issue, and with the scientific and technologic knowledge already in existence.” Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005). In Ariad, the Federal Circuit explained what is required to meet the written description requirement:
This inquiry, as we have long held, is a question of fact. Ralston Purina, 772 F.2d at 575. Thus, we have recognized that determining whether a patent complies with the written description requirement will necessarily vary depending on the context. Capon v. Eshhar, 418 F.3d 1349, 1357–58 (Fed. Cir. 2005). Specifically, the 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. Id. For generic claims, we have set forth a number of factors for evaluating the adequacy of the disclosure, including “the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue.” Id. at 1359.
(Ariad, at 1351).
The written description of a genus, such as a chemical genus, “requires a precise structure, formula, [or] chemical name” of the claimed subject matter sufficient to distinguish it from other materials. Regents of the Univ. of Cal. v. Eli Lilly & Co., 199 F.3d 1559, 1568 (Fed. Cir. 1997). The Federal Circuit commented on that case in the Ariad decision:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus. Id. at 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. at 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001)). 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 that one has invented a genus and not just a species.
(Ariad, at 1350).
The factors outlined in the above Federal Circuit cases are analyzed with respect to the claimed invention in turn below.
(A) The nature and scope of the claim invention in view of the specification: the claimed invention relates generally to the pharmaceutical art, and more specifically:
Claims 1–7, 18, 19, 39–45, and 56 are directed to a method of using a chemical genus, but the chemical compounds in the genus are not characterized by a structure, formula, or name.
Claim 1 is directed to a method of contacting a cell with a “bifunctional compound.” The bifunctional compound comprises: “a first molecule component capable of interacting with a protein kinase C type beta (PKCb1) polypeptide” and “a second molecule component capable of interacting with an E3 ubiquitin ligase polypeptide” covalently connected by a linker.
Claim 39 is directed to a method of administering a “bifunctional compound” that is coextensive with the a “bifunctional compound” in claim 1.
Claims 3 and 41 state the first molecule component comprises “an endoxifen residue,” but do not state what else the bifunctional compound includes.
Claims 4 and 42 state the second molecule component comprises “an immunomodulatory drug (IMiD) residue,” but do not state what else the bifunctional compound includes.
Claims 5 and 43 state the second molecule component comprises “a thalidomide residue,” but do not state what else the bifunctional compound includes.
The claims do not define the structure of molecules capable of interacting with a protein kinase C type beta (PKCb1) polypeptide; or the structure of molecules capable of interacting with an E3 ubiquitin ligase polypeptide. The claimed bifunctional compound is defined by a property that is inherent to the molecules: capable of interacting—a term that is broad in scope. A molecule only has to be “capable” of direct or indirect interaction with the target and any quantifiable amount of interaction is sufficient. The actual scope of bifunctional compound in claims 1 and 39 is indeterminate. To estimate its scope, the subgenus according to Formula (A) in claim 8 can be considered. That formula covers thousands of different compounds based on the options for the variables (L1, L2, R1, RN, n). In view of the scope of Formula (A), the relative scope of compounds in claims 1 and 39 (which are limited by no structure) would be magnitudes greater and could encompass millions of different compounds.
The specification, drawings, and claims disclose specific examples of a bifunctional compound. In each example, the first molecule component is an endoxifen residue. Endoxifen,
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, is a metabolite of tamoxifen,
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(an existing cancer drug). In each example, the second molecule component is
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, which includes a bicyclic ring having an oxo-isoindole moiety and a 2,6-dioxopiperidine moiety. The oxo-isoindole moiety comprises a phenyl moiety through which the linker is bound. The second molecule component in the examples is structurally similar to thalidomide,
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, but the examples do not have a dioxo-isoindole moiety. The second molecule component in the examples is structurally similar to lenalidomide,
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., but do not have an amine. (Spec., pp.3–31; 41–44; 46–48; FIGs. 2A–2J; 8A–8F).
The specification does not disclose any specific examples of bifunctional compounds in which the first molecule component or the second molecule component is something other than those components described in the above paragraph.
The specification does not disclose any examples of compounds in which the second molecule component comprises a thalidomide residue. In each example, the linker is covalently bonded to the phenyl of the oxo-isoindole moiety in the second molecule component structure.
Comparing the claims drafted with broad, functional language with the specification disclosing specific compounds of Formula (A), one of ordinary skill in the art would appreciate the scope of compounds encompassed by the claimed genus is disproportionately larger than the disclosure of species within that genus.
(B) The extent and content of the prior art: relevant prior art is cited herewith. The cited references show claimed subject matter that was known or would have been obvious to one of ordinary skill in the art at the time of invention. Applicant’s disclosure is therefore critical to show possession of novel and nonobvious compounds and methods of using the same.
(C) The maturity of the science or technology: tamoxifen and related compounds are known and have been used to treat cancer. The relevant prior art discloses bifunctional compounds having an endoxifen residue, a linker, and a portion structurally similar to the other component. Thus, the science is generally mature.
(D) The predictability of the aspect at issue: the pharmaceutical art is generally recognized as unpredictable. In re Fisher, 427 F.2d 833, 839 (CCPA 1970). The art requires each potential drug candidate to be assessed for physiological activity. (Id.). The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement. In this case, the Specification discloses structurally similar compounds (TC-Pr-001 and TC-Pr-007) can exhibit significantly different biological activities, as shown in Tables 1 and 2 (below).
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Thus, the claimed invention is no more predictable than the pharmaceutical art is generally, and each compound must be assessed for its own physiological activity and therapeutic potential.
The question of written description
When the above factors and evidence of record are considered as a whole, a conclusion that the specification does not adequately describe a representative number of species to support the claimed compounds and methods of using the same is unavoidable. The scope of the claimed invention is disproportionate in scope relative to the disclosure in the specification, the nature of the invention is complex (pharmaceutical art), and the invention is unpredictable. Although the level of ordinary skill in the art is high and the prior art discloses embodiments within the scope of invention, a representative number of patentable species for the claimed genus is lacking. Thus, the specification would not reasonably convey to those skilled in the art the inventor had possession of the claimed subject matter as of the filing date.
Examiner recommends amending claims 1 and 39 to incorporate the structural features of claims 8 and 46, respectively.
Claim Rejections - 35 U.S.C. § 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 1–5, 18, 19, 39–43, and 56 are rejected under 35 U.S.C. §§ 102(a)(1) and (a)(2) as being anticipated by US 2020/0157078 A1 (“Fan”) [IDS] as evidenced by Kareva et al., Frontiers in Ecology and Evolution (2021), 9, Article 673082 (15 pages) (“Kareva”).
Fan discloses compounds having estrogen receptor alpha degradation activity. (Fan, ¶2). Fan discloses compounds according to Formulae (I) and (II):
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(Id., ¶¶9, 22).
Fan discloses bifunctional compounds comprising an endoxifen residue (the entire molecule but for the functional group used for conjugation to a linker) that is linked to the structure
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, including, for example:
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(Id., p.27).
Fan discloses administering the disclosed compounds to treat cancer, including breast cancer. (Id., ¶¶503–512; claims 28–30).
Fan discloses contacting human breast cancer cells (T47D) with a compound. (Id., ¶634).
Kareva explains that a portion of the patient population possesses ER+ and ER- cancer cells. (Kareva, FIG. 5, p.11).
Because Fan discloses administering the compounds to treat patients having breast cancer and a portion of the patient population possesses ER+ and ER- cancer cells, it follows that Fan inherently discloses administering the compounds to treat patients having ER- cancer cells.
Claim Rejections - 35 U.S.C. § 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.
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.
Graham v. John Deere Co., 383 U.S. 1, 17 (1966); MPEP § 2141(II).
Claims 6, 7, 44, and 45 are rejected under 35 U.S.C. § 103 as being unpatentable over US 2020/0157078 A1 (“Fan”) in view of Dai et al., Journal of Cancer (2017), 8, 3131–3141 (“Dai”).
The Graham factors are addressed in turn below.
Determining the scope and contents of the prior art
The discussion of Fan in the anticipation rejection above is incorporated herein.
Ascertaining the differences between the prior art and the claims at issue
Fan does not disclose a compound having an IC50 of less than 500 nM in a crystal violet proliferation assay using triple negative cells, as recited in claim 6; or the triple negative cells BT549 or MDAMB436 recited in claim 7.
Dai discloses 84 breast cancer cell lines, including BT549 and MDAMB436. (Dai, pp.3133–3134, Table 1). Dai discloses BT549 and MDAMB436 are triple negative breast cancer cells. (Id.).
Dai discloses a summary and categorization of available cell lines, which assists those having of ordinary skill in the art with selecting models for particular cancer subtypes.
By summarizing and going through all the molecular features of currently available cell lines, we grouped them using a subtyping system compatible with that in tumors, and clarified some ambiguous information regarding cell molecular and morphological features. This helps us in the proper choice of and widens the selection spectrum of cell lines when conducting relevant studies, which is critical in the guarantee of final success of translating cell line based results to clinics.
(Id., 3139).
Resolving the level of ordinary skill in the pertinent art
The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
Considering objective evidence present in the application indicating obviousness or nonobviousness
The instant application includes data in Table 1 for 10 compounds—some of which having an IC50 of less than 500 nM in a crystal violet proliferation assay—while others do not.
The question of obviousness
Based on the above factors, it would have been obvious for a person having ordinary skill in the art prior to the filing of the instant application to arrive at the claimed methods because Fan discloses a method of treating breast cancer with compounds within the scope of claims 1 and 39, and the IC50 value is an intended result or property of the compound and, therefore, inseparable from the compounds; and the triple negative cells BT549 or MDAMB436 were known options for use as a model for triple negative breast cancer. As such, one of ordinary skill in the art would have been motivated to screen compounds within the scope of the claims against the triple negative cells in order to improve the efficacy of the cancer treatment. There would have been a reasonable expectation of success at arriving at the claimed invention because the limited data provided in Table 1 of the specification suggests that about half of the compounds would possess the intended result or property of the compound.
The instant application does not include evidence of unexpected results commensurate in scope with the claims. As noted, the scope of claims 1 and 39 encompasses hundreds, thousands, or millions of different compounds. By contrast, the data in Table 1 is for 10 compounds. Moreover, several of the tested compounds do not have an IC50 of less than 500 nM in a crystal violet proliferation assay and therefore do not fall within the scope of the claims.
Allowable Subject Matter
Claims 8, 9, 14, 46, 47, 52, 76, 77, 81, and 86 are allowed.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jason Nolan at (571) 272-2480. The examiner can normally be reached Monday through Friday between 9:00–5:00.
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/JASON M. NOLAN/Patent Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623