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 .
Response to Amendment
The amendment filed 2025 October 29 containing newly amended claims 1-3, 5-10 and 13-16 is examined on the merits. The 35 U.S.C. 102(a)(1) rejections are maintained because the attached translations of the Chinese foreign priority documents are not certified [see MPEP 213, 37 CFR 1.55 (g)(4)]. Due to the lack of any bibliographic information in each translation, it is hard to tell which translation is which foreign priority document.
Claim Objections
Claims 1-3 and 5 are objected to because of the following informalities: the language “and the pharmaceutically acceptable salt, hydrate, or solvent mixture thereof” should be written as –-or the pharmaceutically acceptable salt, hydrate, or solvent mixture thereof-- because each of these forms is an alternative form of a compound of formula (I-2). 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 10 is 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 first reaction of claim 10 represent new matter because variable R1 is attached to a p-OMe phenyl ring.
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Paragraph [0093] of the specification recites the following synthetic step.
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Based on the different variable attached to the bottom left phenyl ring, claim 10 represents new matter,
Claims 6-8 and 14-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification is enabling for the treatment of a disease selected from the group consisting of mammalian diseases associated with tubulin aggregation and angiogenesis with a compound of formula (I-2) and non-enabling for the prevention of a disease selected from the group consisting of mammalian diseases associated with tubulin aggregation and angiogenesis with a compound of formula (I-2). 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/or use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth herein below:
The nature of the invention and (2) the breadth of the claims:
The claims are drawn to treatment or prevention of a disease selected from the group consisting of mammalian diseases associated with tubulin aggregation and angiogenesis with a compound of formula (I-2). Thus, the claims taken together with the specification imply a compound of formula (I-2) can treat or prevent a disease selected from the group consisting of mammalian diseases associated with tubulin aggregation and angiogenesis.
The state of the prior art and (4) the predictability or unpredictability of the art:
PRICHARD (British Journal of Surgery 2003, 90, 772-783) describes that the chance of getting breast can be reduced through chemoprevention by 32%. This reduction is not equivalent to prevention.
The relative skill of those in the art:
While the artisan generally would have an advanced degree in prevention of cancer, their high level of skill and knowledge is insufficient to overcome the lack of understanding as to how cancer functions in the body or to overcome the art recognition that this disease is poorly understood and treatments have generally failed.
The amount of direction or guidance presented and the presence or absence of working examples:
The specification has provided guidance for the treatment of a disease selected from the group consisting of mammalian diseases associated with tubulin aggregation and angiogenesis with a compound of formula (I-2).
The specification does not provide guidance for the prevention of a disease selected from the group consisting of mammalian diseases associated with tubulin aggregation and angiogenesis with a compound of formula (I-2).
The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to chemoprevention of cancer and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
Claims 1-3, 5-8, 10, and 14-16 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 and 5 recite the limitation “and the pharmaceutically acceptable salt, hydrate, or solvent mixture thereof”. There is insufficient antecedent basis for this limitation in the claims because when the word “the” is used it assumed a previous reference is made to a limitation. In the case of claim 1, it is the first reference to a pharmaceutically acceptable salt, hydrate, solvent mixture thereof. Following this rationale, the phrase “and the pharmaceutically acceptable salt, hydrate, or solvent mixture thereof” should be written as “and a pharmaceutically acceptable salt, hydrate, or solvent mixture thereof”.
Claim 2 lacks antecedent basis to claim 1 for the following reasons: geminal variables R3 and R4 represent CH2-R and OR; and variable R1 in claim 2 has unclear metes and bounds. Is R1 intended to be the same variable R in claim 1?
What are the metes and bounds of variable R1 in claims 2 and 10? Claim 1 has been amended that R1 is no longer needed.
Claim 5 recites compounds in which one of variable R3 or R4 is OH. Compounds 72, 80, 82, 84, 94, and 95 are compounds in which this condition is present. There is insufficient antecedent basis for these compounds in the claim because the hydroxy limitation has been removed as a possibility and variable R cannot be hydrogen.
Claims 6-8 and 14-16 refer back to a pharmaceutical composition of claim 1 and 13 respectively. There is insufficient antecedent basis for this limitation in the claim because claims 1 and 13 are each compound claims, not pharmaceutical composition claims.
Claim 10 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: the reagents and reactants required for the conversion of a compound of formula If to a compound of formula Ig; and the reagents and reactants required for the conversion of a compound of formula Ig to a compound of formula I-2..
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:
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.
Claim(s) 1, 5, and 9 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by XU (Journal of Chromatography B, 2019, 1121, 66-71). Xu describes compound WY-Z1A which is selected species 69 (page 70, figure 5). In this compound the following examined definitions apply: variable R2 represents one meta-OH; variables (R3, R4) represent (H, CH2OH). Pharmaceutical compositions are described (page 70, section 3.4).
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Claim(s) 1, 2, 5-9, and 13-16 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by ZHOU (European Journal of Medicinal Chemistry, 2018, 144, 817-842). Zhou describes the following compounds: compounds 3, 4, 11e-h, 11j, 12a-h, 13a, 13b, 14a-j , 16b, 18a, 19, 21, 22, 24, 25, and 26a-c (page 818, figure 1; page 819, scheme 1; page 820, schemes 2 and 3; page 821, schemes 4 and 5). Pharmaceutical compositions are described (pages 822-823, section 2.2.4; page 824, section 2.2.7). In these compounds the following examined definitions apply: variable R2 is selected from OH, F, Cl, NH2, NHC(O)-CH=CH, OMe, OEt, OPr-n, OPr-i, Obenzyl, OC(O)Me, OSO2-p-me-phenyl; OSO2NH2; variables (R3, R4) are selected form the group consisting of: a =CH2 group; a CH-[phenyl or p-t-butyl-phenyl] group; or the substituents (Me, H), (H, CH2OH), (H, CH2NH2), (H, CH2OMe), (H, CH2NMe2), (H, OSO2-Me), (CH2OMe, OMe), (H, OMe), (OH, H), [H, NHC(O)Me], [H, C(O)phenyl], [NH-SO2Me], (CH2OH, H), (H, Me), or (H, Br), Compound 17 is the same as compound 72 of claim 5. Compound 24 is the same as compound 66 of claim 5. Compound 24 is the same as compound 61 of claim 13. In vivo anti-vascular activity and tubulin activity is described (section 2.2.4, pages 822-823; pages 824-827, sections 2.2.7 and 2.2.8). Ovarian cancer is treated in mice models.
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Response to Arguments
These rejections are maintained because the provided translations are not certified. Additionally, due to the lack of bibliographic information in each translation, it is difficult to determine which translation corresponds to each priority document.
Claim(s) 1 and 6-9 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by MEEGAN (WO 2011073211, published 2011 June 23). Meegan describes compounds 3, 6, 25, and 28 (page 25, paragraph [0144], table 1). In these compounds, the following examined definitions apply: R2 is OH; and (R3, R4) is [H, CH=CH(CH3)], [CH=CH(Me), H], [H, CH(OH)Me], [CH(OH)Me, H], (H, H), (CH3, H), or (H, CH3). These compounds were tested against breast cancer cell line MCF-7 and are inhibitors of tubulin formation (page 21, paragraph [0117]; page 42 paragraph [0189] to page 43, paragraph [0190]). Pharmaceutical compositions are described (page 54, claim 8).
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Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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, 5, and 9 are rejected under 35 U.S.C. 103(a) as being unpatentable over XU (Journal of Chromatography B, 2019, 1121, 66-71).
Determining the scope and contents of the prior art
Xu describes compound WY-Z1B, a diastereomer of compound 69 (page 70, figure 5). In this compound the following examined definitions apply: variable R2 represents one meta-OH; variables (R3, R4) represent (CH2OH, H). The relationship of the 3-OH, 4-OMe-phenyl group and the CH2OH is a syn relationship. Both of these compounds are antimitotic compounds (page 70, second column, second paragraph).. Pharmaceutical compositions are described (page 70, section 3.4).
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Ascertaining the differences between the prior art and the claims at issue
In the prior art, a anti diastereomer of compound 69 is described.
Resolving the level of ordinary skill in the pertinent art
Those of relative skill in the art are those with level of skill of the authors of the references cited to support the examiner’s position (MD’s, PhD’s, or those with advanced degrees and the requisite experience in preparation of compounds of the elected group).
Considering objective evidence present in the application indicating obviousness or nonobviousness
Xu describes that a reasonable expectation of success is present to create a diastereomer of compound 69 is present because both diastereomers are antimitotic compounds. Figure 5 shows that both compounds affect tubulin binding. Based on these teachings, diastereomer WY-Z1B is an obvious variant of WY-Z1A.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 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. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary 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.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Claims 1, 5, and 10 are rejected under 35 U.S.C. 103(a) as being unpatentable over ZHOU (European Journal of Medicinal Chemistry, 2018, 144, 817-842).
Determining the scope and contents of the prior art
Zhou describes a synthetic sequence (page 821, scheme 5). In this sequence, compound 27 is converted to compound 30 through three synthetic steps.
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Compounds 30a, 30b, and 30d, and 30e are 4S diastereomers of 3S enantiomers 14a-g, These compound have antiproliferative activities (page 822, table 1).
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Ascertaining the differences between the prior art and the claims at issue
In the prior art, a 4R diastereomer is synthetically prepared and used as antiproliferative compounds. In the claims at issue, a 3R diastereomer is synthetically prepared.
Resolving the level of ordinary skill in the pertinent art
Those of relative skill in the art are those with level of skill of the authors of the references cited to support the examiner’s position (MD’s, PhD’s, or those with advanced degrees and the requisite experience in preparation of compounds of the elected group).
Considering objective evidence present in the application indicating obviousness or nonobviousness
Zhou describes that a synthetic process in which a 4S diastereomer is used as a reactant has success because the synthetic process leads to a mixture of different products. Compounds 30a-d, 4S diastereomers, of 3S diastereomers, show antiproliferative activity against four different cell lines. Based on the common shared antiproliferative activity of compounds 14a-g and 30a-d, a reasonable expectation to have a 4S center versus a 3S center in antiproliferative β-lactam compound is present.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 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. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Conclusion
Claims 1-3, 5-10, and 13-16 are not allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NOBLE E JARRELL whose telephone number is (571)272-9077. The examiner can normally be reached 9:00 AM to 5:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Fereydoun Sajjadi can be reached at 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NOBLE E JARRELL/Primary Examiner, Art Unit 1699