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 .
Claim Status
Claims 1-18, and 23-29 are pending.
Claims 8, 9, 11-18, and 23-26 are withdrawn (see restriction/election below).
Priority
This application is filed 04/25/2024, and claims the benefit of domestic priority as below:
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Information Disclosure Statements
Three IDS(s) received on 04/25/2024, 11/18/2025, and 02/032/2026 have been considered unless marked with a strikethrough.
Election/Restrictions
Applicant’s election of compound E14 in claim 27 as a species, and multiple myeloma as the specific disease species in the reply filed on 07/27/2026 is acknowledged. Although Applicant stated “without acceding to the Examiner's assertions”, because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant asserts that claims 1-5, 9, 11, 13-18, 24, and 26-29 read on the elected species.
If the elected specie is not identified in the prior arts, the elected specie would be allowable if an independent claim were drafted with that specie alone, and Examiner expanded the search to additional species of the genus per MPEP 802.03.
The elected specie was not identified in the art. Examiner expanded his search to a new specie pursuant to MPEP 803.02. The alternative species, E04 in claim 27, is identified that would have been obvious to a person of ordinary skill in the art, and Formula (I) as the genus of E04 would have been anticipated. Thus, the expanded specie reads on claims 1-7, 10 and 27-29. Claims 8, 9, 11-18, and 23-26 are withdrawn as not reading on the expanded specie. It should be noted that the full scope of claims 8, 9, 11-18, and 23-26 have not yet been searched. Accordingly, claims 1-7, 10 and 27-29 will be examined on their merits.
With respect to the expanded species, the art is rejected under 35 USC 102 and 35 USC 103 below.
Claim Objections
Claim(s) 1 is/are objected to because of the following informalities:
Claim 1 is objected to because the term “cyclylene” should be “cycloalkyene”.
Claim 1 is objected to because the term “oligo peptide” should be “oligopeptide” for consistency.
Appropriate correction is required.
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.
Claim 29 is 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 the preparation and conjugation of the claimed compounds, including antibody conjugates, does not reasonably provide enablement for the full scope of using the broad genus of compounds encompassed by claim 1 to treat any disease or disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: 1) the quantity of experimentation necessary; 2) the amount of direction or guidance provided; 3) the presence or absence of working examples; 4) the nature of the invention; 5) the state of the prior art; 6) the relative skill of those in the art; 7) the predictability of the art; and 8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Nature of the invention:
The invention is drawn to 1,2-dihydro-3,6-pyridazinedione based heterobicyclic likers and compounds comprising such linkers. Claim 29 broadly recites a method of treating a disease or disorder by administering a compound according to claim 1, or a pharmaceutically acceptable salt thereof. The specification describes antibody drug conjugates (ADC) for a cancer antigen.
Breadth of the claims:
The claims are broadly recited “a method of treating a disease or disorder” without limitation to any particular disease or disorder, antigen, antibody, payload, or patient population. Thus, the claim encompass treatment of any disease or disorder using the broad genus of compounds encompassed by claim 1.
Level of ordinary skill in the art:
The level of ordinary skill in the art would include medicinal and synthetic chemists, bioconjugation scientists, molecular and cellular biologists, and clinicians having experience with targeted therapeutic agents.
However, even if a PHOSITA possesses a high level of technical knowledge, this does not enable them to predict the unpredictable biological responses that may arise when treating any disease or disorder using the broad genus of compounds encompassed by claim 1. Moreover, the scope of enablement required in the fields of physiology and pharmacology is inversely proportional to the degree of predictability in the technology. See MPEP 2164.03; in re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970)
State of the prior art and predictability in the art:
Khongorzul et al. (Antibody-Drug Conjugates: A Comprehensive Review., Mol. Cancer Res., 18(1), 3-19, pub’d 10/28/2019) describes ADC as targeted anticancer agents in which a monoclonal antibody directs a cytotoxic payload to an antigen expressed on the cancer cell surface, reducing systemic exposure and therefore toxicity (abstract). Khongorzul supports that the therapeutic activity of ADCs depends on several interrelated factors, including the characteristics and expression of the target antigen, the antibody, the cytotoxic payload, and the linker/conjugation chemistry.
Therefore, the therapeutic efficacy of a specific ADC for a limited set of diseases cannot reasonably demonstrate that the structurally and functionally diverse compounds encompassed by claim 1 are capable of treating the entire range of diseases and disorders encompassed by claim 29. In addition, pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The amount of direction provided and working examples:
The specification provides that the disclosed compounds may be used to trat a disease or disorder and defines “treating” as inhibiting or relieving a disease , disorder or conditions. The working examples of the instant specification show that preparation of an antibody/SBC linker/MMAF conjugate and a predominantly DAR4 conjugate, but does not provide a working therapeutic example demonstrating treatment of a particular disease with the claimed method. Accordingly, the scope of claim 29 exceeds that of the currently presented examples. See MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed ... Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.”).
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. See MPEP 2164.01 and 2164.06.
For claim 29, in view of Khongorzul, a person skilled in the art would select an appropriate therapeutic moiety or antibody, identify a disease-associated target, establish appropriate target expression, prepare a corresponding conjugate or compound, and then experimentally verify whether the resulting compound possesses therapeutic activity against a specific disease or disorder.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation.
Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent 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”.
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 1-7, 10, 28 and 29 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.
Regarding claim 1, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 2-7, 10, 28 and 29 depend directly or indirectly from claim 1. These dependent claims incorporate the same indefinite Formula 1 definitions as the same reason.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-7, 10 and 27-29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Park et al. (KR 2019-0143246 A, pub'd 12/30/2019).
With respect to independent claim 1, the claim recites that a compound of formula (I) and (II).
Park teaches a compound of Formula A. Park defines that YA and YB as each independently selected from halogen; XA and XB as each independently selected from oxygen; n=1~4; and R1 as variable point of attachment can be a carbonyl group, a carboxyl group, an alkyl group, an aryl group, a heteroaryl group and an amine group (claim 1). Park further teaches specific species falling within Formula A. For example, the species disclosed in connection with paragraph [0260]’s compound of Park corresponds to the instant Formula (I) in which X and X’ are oxygen, R2a and R3a are Br, m is 1, n is 2, and Y-L-R1 corresponds to -C(O)O-alkyl. Park also permits the position of R1 can be a variable point of attachment (VAP).
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Park’s Formula A Park’s species Instant Formula (I) Instant species E04
Park further teaches 1) the compounds are relating to a linker compound, and relates to a site-specific antibody-drug conjugate (ADC) compound comprising the same, a method for manufacturing the same, and an anticancer composition comprising the same as an active component; and 2) the linker compound produces a uniform ADC compound with excellent site specificity in manufacturing an ADC compound, and the ADC compound comprising the same exhibits an excellent anticancer effect (abstract).
Park fails to teach the specific species of Formula (I) or (II).
However, Formula A discloses the claimed compounds through sufficiently limited and clearly defined substituent options. In particular, when compared to the compounds specifically exemplified in the Park document, arriving at the presently claimed compounds requires selecting n=1 and m=1, as well as the Y-L-R1 group at the corresponding positions. These structural alternatives fall within the scope of the alternatives explicitly presented for Formula A in the Park document and represent selection therefrom. For example, to arrive at instant species E04 from Park’s genus, Park defines that 1) five membered ring; 2) variable attachment of the COO-alkyl group containing R1 group at the carbon positions encompassing the position recited in E04; 3) the bond of R2a carbon and R3a carbon forms a double bond; 4) X and X' are each O; and 5) R2a and R3a are each bromo (Br).
It would have been obvious to a PHOSITA at the time of the invention to select the claimed ring size, attachment position, and R substituents from the finite and predictable structural alternatives taught by park. These selection include a ring having fewer methylene (-CH2-) group and a methyl group in the alcohol derived portion of the ester. Because Park permits these alternatives within Formula A, a skilled artisan would have had reasonably expected the resulting compound to retain the properties and utility of Park’s disclosed compounds. Such a modification would have been expected to yield a structurally similar compound with a reasonable expectation of success. (See MPEP 2413 and 2143.01)
The references is directed to the same field of endeavor and address related to the application. The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Consistently, applying KSR example rationale (E) in the independent claim 1, it would have been prima facie obvious to select from a finite number of identified by Park, including ring size, attachment positions, and R groups. Thus, the species, including E04, are obtained by making a selection from the finite number taught by Park, yielding predictable results. (see MPEP 2141)
With respect to claims 2-7 and 10, the claims recite that the alternatives of Ring A, m/n values, bond type between R2a carbon and R3a carbon, X, X', R2a, R3a , Y, L, and R1.
Park’s Formula A teaches Ring A is a 5 membered heterocycle and m and n are each independently 1, as required in claims 2-4; R2a carbon and R3a carbon is a double bond, and X and X' are each O, as required in claim 5; R2a and R3a are each bromo (Br), as required in claims 6 and 7; Y is -C(O)O-, L is a bond, and R1 is alkyl , as required in claim 10. Thus, claims 2-7 and 10 would have been obvious for the same reasons discussed with respect to claim 1.
With respect to claim 27, the claim recites that a compound selected from compounds E1 through E15 and E17 through E24, or a salt or stereoisomer thereof.
Park fails to teach the specific compounds that exactly matches the compound specified in claim 27.
However, Formula A discloses the claimed compounds through sufficiently limited and clearly defined substituent options. For example, Park teaches that the compounds,
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and
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in paragraphs [0260] and [0266], and as discussed above with respect to claim 1, Park further teaches 1) five membered rings; 2) variable attachment of the COOH and COO-alkyl group containing R1 group at the carbon positions encompassing the position recited in E03 and E04; 3) R2a carbon and R3a carbon is a double bond; 4) X and X' are each O; and 5) R2a and R3a are each bromo (Br). Thus, claim 27 would have been obvious for the same reasons discussed with respect to claim 1.
With respect to claim 28, the claim recites that a pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
Park teaches pharmaceutical formulations containing an ADC compound and a pharmaceutically acceptable vehicle. In the working examples 3-1, park formulates ADC compound X-2 in D-PBS for administration to nude mice bearing BT-474 human breast cancer xenografts (paragraphs [0741]-[0766]).
With respect to claim 29, the claim recites that a method of treating a disease or disorder, comprising administering to a subject in need thereof a compound according to claim 1, or a pharmaceutically acceptable salt thereof.
Park teaches administering ADC compound X-2 intravenously to nude mice implanted with BT-474 human breast cancer cells and evaluating inhibition of tumor growth (paragraphs [0741]-[0766]). Thus, Park discloses a method of treating a disease or disorder by administering a compound falling within the claimed scope to a subject in need thereof.
Conclusion
Claims 1-7, 10 and 27-29 are rejected.
Claim 1 is objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEONG JONG KIM whose telephone number is (571)272-6918. The examiner can normally be reached 7:00am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621
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