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 22 May 2023 has been examined.
Claims 1–11 are pending. Claims 4–9 are amended. Claims 10 and 11 are new.
Priority
The instant application was filed 22 May 2023; is a national stage application of PCT/JP2021/037805, filed 13 October 2021, and claims priority to JP 2020-178209, filed 23 October 2020. Acknowledgment is made of applicant’s claim for foreign priority and a copy of the priority document has been received.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 22 May 2023 is acknowledged and has been considered.
Claim Rejections - 35 U.S.C. § 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 MPEP explains the purposes of the definiteness requirement relate to clarity:
The primary purpose of this requirement of definiteness of claim language is to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent. A secondary purpose is to provide a clear measure of what the inventor or a joint inventor regards as the invention so that it can be determined whether the claimed invention meets all the criteria for patentability.
MPEP § 2173.02 (emphasis added).
The Federal Circuit has stated the patent drafter is in the best position to improve clarity by resolving any ambiguities in a claim during prosecution:
We note that the patent drafter is in the best position to resolve the ambiguity in the patent claims, and it is highly desirable that patent examiners demand that applicants do so in appropriate circumstances so that the patent can be amended during prosecution rather than attempting to resolve the ambiguity in litigation.
Halliburton v. M-I LLC, 514 F.3d 1244, 1249 (Fed. Cir. 2008).
(i) Claims 1–5 and 7–11 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The claimed invention is directed to a complex comprising a compound of Formula (1), a linker, and a leaving site having another chemical structure. The leaving site is connected to the compound of Formula (1) via the linker. The linker is cleavable by a reaction with acrolein, which makes the complex a prodrug for delivering the leaving site to a biological target.
The names or chemical structures of the leaving site is not defined in claim 1, so a skilled artisan would not be apprised of the metes bounds of the claims. The recitation of “another chemical structure” may reasonably refer to a different chemical structure from Formula (1) or an additional chemical structure to Formula (1) or of Formula (1).
Claim 6, which is not included in this rejection, recites “the leaving site is an antitumor compound.” The specification defines “antitumor compound” as follows:
As an antitumor compound used as the leaving site, all compounds including antitumor compounds that are used in clinical practice or clinical test and antitumor compounds that will be developed in the future can be used without limitation, provided that the compounds each have activity of killing a tumor cell in a living organism, like an anticancer drug, a low-molecular target agent, a radionuclide, and the like.
(Spec., p.22, ¶51). The antitumor compound is therefore defined by its function of killing a tumor cell in a living organism, but not limited to any structure. The scope of antitumor compound is broad but not indefinite.
Claim 7 recites, “the leaving site leaves by reacting with acrolein that is present around a tumor cell.” The claim recites an intended result, which in this case does not define the leaving site; and therefore, does not particularly point out and distinctly claim the subject matter.
Examiner recommends amending claim 1 to include the subject matter of claim 6 to overcome this rejection; however, the written description rejection below must also be addressed.
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 1–11 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 is directed to the pharmaceutical art and more specifically to a complex comprising a compound of Formula (1), a linker, and a leaving site. The linker connects the leaving site to the compound of Formula (1). The linker is cleavable by a reaction with acrolein.
The chemical structure of Formula (1) is defined in claim 1.
The chemical structure of the linker is not defined in claim 1. A chemical structure of a linker is provided in claims 2–4 as Formula (2), which is an alkyl-ester moiety. The specification states the chemical structure defined as Formula (2) is an “example” of a linker. (Spec., p.15–20; ¶¶32–46). The specification does not disclose alternative examples or disclose generally which chemical structures are cleavable by a reaction with acrolein. Accordingly, the scope of the claimed “linker” cannot be determined outside of claims 2–4.
The chemical structure of the leaving site (claim 1 recites, “a leaving site having another chemical structure”) is not defined in the claims. Claim 6 defines the leaving site as “an antitumor compound.” The specification defines “antitumor compound” as follows:
As an antitumor compound used as the leaving site, all compounds including antitumor compounds that are used in clinical practice or clinical test and antitumor compounds that will be developed in the future can be used without limitation, provided that the compounds each have activity of killing a tumor cell in a living organism, like an anticancer drug, a low-molecular target agent, a radionuclide, and the like.
(Spec., p.22, ¶51).
The Specification provides several examples of antitumor compounds:
Examples of the antitumor compound suitably used as the leaving site include, but not limited to, mitomycin C, doxorubicin, dacarbazine, crizotinib, endoxifen, and a camptothecin derivative [e.g., an active body part of DS-8201 (trastuzumab deruxtecan) (code name: DXd, chemical name: N[(1-S,9S)-9-ethyl-5-fluoro-2,3,9,10,13,15-hexahydro-9-hydroxy-4-methyl-10,13-dioxo-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-1-yl]-2-hydroxyacetamide, see Drug Delivery System Vol. 34, No. 1 (2019) p. 52-58, “Development of novel DNA topoisomerase I inhibitor based ADC technology” by Yuki Abe, Takashi Nakada, and Toshinori Agatsuma)].
(Id., p.23; ¶51); (see also id., pp.23–26; ¶¶55–59).
Based on the disclosures in the specification, the claims encompass any compound possessing activity in killing a tumor cell in a living organism, including anticancer compounds that were not known and had not been discovered at the time instant application was filed (i.e., future compounds). Accordingly, the scope of the claimed “leaving site” extends beyond what is disclosed in the specification.
(B) The extent and content of the prior art: Examiner is not aware of prior art that shows the claimed but not described subject matter would have been known or obvious to one of ordinary skill in the art. Accordingly, Applicant’s disclosure is critical for showing possession.
(C) The maturity of the science or technology: the instant specification states: “use of a compound in a prodrug or the like has not been substantially studied previously.” (Spec., p.3; ¶8). Based on the disclosure, the maturity of the science is in its infancy.
(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, there is no evidence suggesting the claimed invention is more predictable than the pharmaceutical art is generally.
The question of written description
When the above factors and the evidence of record are considered as a whole, the Specification (in view of the prior art) does not adequately describe a representative number of species to support the claimed invention to a complex comprising a compound of Formula (1), a linker, and a leaving site. Regarding linker, the Specification discloses only the compounds covered by Formula (2). Regarding leaving site, the Specification discloses a list of specific antitumor compounds. Other options would have to be discovered elsewhere. For these reasons, 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 claim 1 to include the subject matter of claim 2 and the specific antitumor compounds recited in the Specification.
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.
Claims 1–4, 6–8, and 10 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Brakel et al., Bioconjugate Chem. (2008), 19, 714–718 (“Brakel”) [IDS].
Regarding claims 1–4 and 6, Brakel discloses compound 2b, which is a complex comprising an acrolein-reactive site having the structure of Formula (1) when each of R1, R2, R3, R4 = H; a leaving site having another chemical structure (doxorubicin), and a linker having the structure of Formula (2) when R = H; and binding site ** to a N atom; as shown below. (Brakel, p.715; Scheme 2).
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Regarding claim 8, Brakel discloses a composition comprising the compound 2b is active in an assay with A431 human vulvar skin squamous carcinoma cells when it is in the presence of compound 1b, which causes the release of the active agent (doxorubicin) in the cell. (Id., 717).
Regarding claims 7 and 10, the phrase “the leaving site leaves by reacting with acrolein that is present around a tumor cell” is intended use language that applies only when the complex is administered to a tumor cell comprising acrolein. Because the complex disclosed in Brakel is capable of reacting with acrolein around a tumor cell because it fulfils the structural requirements of the claim, Brakel’s disclosure of the complex is deemed to read on the intended use language.
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).
Claim 5 is rejected under 35 U.S.C. § 103 as being unpatentable over Brakel in view of Yoshida et al., Scientific Reports (2011), 1(82), 1–4 (“Yoshida”).
The Graham factors are addressed in turn below.
Determining the scope and contents of the prior art
Brakel discloses compound 2b, which is a complex comprising an acrolein-reactive site having the structure of Formula (1) when each of R1, R2, R3, R4 = H; a leaving site having another chemical structure (doxorubicin), and a linker having the structure of Formula (2) when R = H; and binding site ** to a N atom; as shown in rejection above. (Brakel, p.715; Scheme 2).
Yoshida discloses a methodology that increases the rate of reaction in a 1,3-dipolar cycloaddition reaction between an alkyne and 2,6-disubstituted phenyl azides relative to the same reaction with unsubstituted phenyl azides. (Yoshida, p.3).
Yoshida states, “the enhanced reactivity of the 2,6-disubstituted phenyl azides can be attributed to the increased distortability of the azido group elicited by the inhibition of resonance with the aromatic ring.” (Id.).
Ascertaining the differences between the prior art and the claims at issue
Brakel does not disclose 2,6-disubstituted phenyl azides. Yoshida is relied on for that claim element.
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
Not applicable. The examples in the instant application do not compare the reaction between acrolein and 2,6-disubstituted phenyl azides relative to unsubstituted phenyl azides.
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 combine the teachings of Brakel and Yoshida to arrive at the complex in claim 5 because Brakel and Yoshida are both directed to reactions between a phenyl azide and unsaturated bonds like those in a 1,3-dipolar cycloaddition.
One of ordinary skill in the art would have been motivated to modify Brakel based on Yoshida because Brakel discloses the structure of Formula (I) and Yohsida states a sterically-congested azido group will react faster with unsaturated bonds like those in a 1,3-dipolar cycloaddition than a corresponding structure without the 2,6-substituents on the phenyl azide. Yoshida explains the steric hindrance on the phenyl azide increases distortability of the azido group elicited by the inhibition of resonance with the aromatic ring. There would have been a reasonable expectation of success at arriving at the claimed invention because Brakel and Yoshida demonstrate how to execute the reaction and the high level of ordinary skill in the art would be capable of applying the combining the disclosures of related reactions.
Conclusion
No claims are allowed.
Communication
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/JASON M. NOLAN/Patent Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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