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 .
Status of the Claims
Acknowledgment is made of Applicant’s amendments filed September 24, 2024.
Claims 1-4, 8, 13, 18, 23, 28, 33, 42, 47-48, 53-54, 59-60, 69, 73, and 75 are pending and currently under examination.
Priority
This application claims foreign priority to PCT/CN2021/115963, filed September 01, 2021, and is a 371 of PCT/IB2022/058131, filed August 30, 2022.
Drawings
Acknowledgment is made of the drawings received February 28, 2024.
The drawings are objected to because of the following reasons:
Fig. 3: The axis labels and curve labels are all pixelated and hard to read.
Fig. 32: The axis labels and curve labels are all pixelated and hard to read.
Fig. 33: The axis labels and curve labels are all pixelated and hard to read.
Fig. 35: The axis labels and curve labels are all pixelated and hard to read.
Fig. 39: The axis labels and curve labels are all pixelated and hard to read.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 4, 48, 54, 59, and 60 are objected to for the following informalities:
Claims 4, 54, and 60 all recite X-ray diffraction peaks in table form, when they should be recited in plain language. For example, claim 4 should read “[…]characterized by an X-ray powder diffraction pattern comprising peaks at four or more 2θ values[…]selected from the group consisting of 11.93° ±0.2°, 13.26° ±0.2°, 13.77° ±0.2°, 15.12° ±0.2°, 16.99° ±0.2°, 17.39° ±0.2°, 19.92° ±0.2°, 20.73° ±0.2°, 21.06° ±0.2°, 23.45° ±0.2°, 24.11 ° ±0.2°, 26.37° ±0.2°, and 26.66° ±0.2°, wherein[…]”. See MPEP 2173.05(s).
Claim 48 is objected to because it is missing a period at the end. Claims must end with a period; see MPEP 608.01(m).
Claim 59 is objected to because it ends with two periods (.) instead of one.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
112(a) – Scope of Enablement
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 73 and 75 are 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 a method of administering Compound B to treat mesothelioma and adenocarcinoma, does not reasonably provide enablement for the treatment of any disease or condition in which YAP overexpression, YAP amplification, or YAP/TAZ-TEAD interaction is implicated, or any cancer in which the same is implicated. 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. This is a scope of enablement rejection.
To be enabling, the specification of the patent application 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 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
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 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). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 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:
1. The nature of the invention, state and predictability of the art, and relative skill of those in the art
The invention relates to a method of treating a disease or condition mediated by YAP overexpression, YAP amplification, and YAP/TAZ-TEAD interaction or a method of treating a cancer or tumor harboring one or more YAP/TAZ fusions; one or more NF2/LATS1/LATS2 truncating mutations or deletions; or one or more functional YAP/TAZ fusions; comprising administering a crystalline form of Compound B.
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art of treating any cancer, the examiner cites Gura et al ("Systems for Identifying New Drugs are Often Faulty"); Johnson et al. ("Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials"); and Kunnumakkara et al (“Cancer drug development: The missing links”).
Gura, cited for evidentiary purposes, teaches that researches face the problem of sifting through potential anticancer agents to find ones promising enough to make human clinical trials worthwhile and further teach that since formal screening began in 1955, many thousands of drugs have shown activity in either cell or animal models, but only 39 have actually been shown useful for chemotherapy (see page 1041, first and second paragraph). Also, with regard to unpredictability, Johnson, also cited for evidentiary purposes, teach that the in vivo activity of 39 different agents in a particular histology in a tumor model did not correlate to activity in the same human cancer (see Results on page 1426). In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. Further, the mode of action of anticancer agents is often unknown or very unpredictable and administration of such agents is often accompanied by undesirable side effects.
Furthermore, with regard to unpredictability, Kunnumakkara, cited for evidentiary purposes, teaches cancer is a group of more than 200 neoplastic diseases caused by diverse deregulated cell signaling cascades (page 633, left, 1st paragraph); consumption of tobacco and alcohol, obesity, insufficient physical activity, exposure to ultraviolet radiation, and various dietary factors which include insufficient fruit, non-starchy vegetables, and fiber; red/processed meat are predicted to be strongly associated with the risk of diverse cancer types; cancer occurs as a result of the dysregulation of as many as 500 different genes which may happen over a very long duration of time (20–30 years) till the symptoms become apparent (page 633, right, last bridge paragraph). Kunnumakkara further teaches there exists a missing connection between preclinical data and clinical findings; although, a significantly huge amount of money is spent in the pre-clinical settings for target validation and drug optimization, most of the therapies fail in the clinical trials till date; this can be due to the reason that the models used in the pre-clinical setting are not the adequate ones to effectively mimic human responses (page 664, right, 2nd paragraph); although highly convenient, cancer cell line models are associated with several limitations as well; for example, existence of genomic instability which may result in differences between the original tumor and the respective cell line, culture conditions that can alter the morphology, gene expression pattern, genomic profile, cellular pathways and culture environment from that of the original tumor, loss of natural tumor heterogeneity; the generic transformations that occur upon culturing of the cancer cells are not restored when regrown in vivo; and cancer cells in the in vitro condition grow in absence of stroma which include lymphatic vessels and blood, associated fibroblasts and immune cells, and lack a complex extracellular matrix; therefore, in vitro data often exhibits fundamental mismatch with those obtained from clinical findings and hence this can be regarded as one prime reason behind the failure of novel drug development (page 665, last bridge paragraph). Kunnumakkara teaches the foremost shortcomings of the use of animal models are their inability to recapitulate the link between the tumor and its microenvironment completely and the requisite of an immunocompromised host; basically, these animal models do not have the ability to reflect all the features of human cancer impeccably. Kunnumakkara teaches despite the advances in understanding of cancer biology and deriving different novel therapeutic targets, the translation of these understanding into therapies is poor due to higher failure rate (90%). The high failure rate could be due to non-consideration of factors such as clinical translation, drug delivery, drug pharmacokinetics, pre-clinical models, and tumor physiology, which are critical factors.
As illustrative of the state of the art of the Hippo pathway, which YAP/TAZ, TEAD, Nf2, LATS1, and LATS2 are implicated in, the examiner cites Cunningham (Clinical Science (2022); 136; 197–222). Cunningham teaches that the Hippo pathway is modulated by genes and activators including LATS1/2, Yap, and Tas (p. 197, para. 1 of Introduction, lines 1-10). This pathway and alterations thereof are implicated in numerous diseases and conditions, including embryogenesis and a wide range of cancers. Overexpression in particular is implicated in a number of cancers (p. 202, Table 1). The inhibition of YAP and YAP/TAZ-TEAD binding is under-developed, especially in vivo, as although inhibition of YAP-TEAD transcription inhibits tumor growth in murine models, there is cytotoxicity associated with this inhibition independent of its effectiveness on cancers (p. 207, para. 3). The authors note that “overall, the context-dependent role the Hippo pathway plays in immune oncology warrants further examination in order to uncover the interplay and complexities between Hippo pathway components and the immune system” (p. 209, para. 3, lines 5-7).
These articles plainly demonstrate that the art of developing and testing anticancer drugs including YAP inhibitors, particularly for use in humans, is extremely unpredictable, particularly in the case of a single compound or genus of compounds being used to treat any and all diseases wherein YAP overexpression, YAP amplification, or YAP/TAZ-TEAD interaction is implicated, as well as treating any and all cancers or tumors harboring one or more YAP/TAZ fusions; one or more NF2/LATS1/LATS2 truncating mutations or deletions; or one or more functional YAP/TAZ fusions.
2. The breadth of the claims
Claims 73 and 75 are very broad in terms of the type of diseases being treated: all diseases and conditions mediated by YAP overexpression, YAP amplification, and YAP/TAZ-TEAD interaction are claimed to be treated by administering Compound B, as well as any cancer or tumor harboring one or more YAP/TAZ fusions; one or more NF2/LATS1/LATS2 truncating mutations or deletions; or one or more functional YAP/TAZ fusions. In addition, “treating” as defined by the specification includes “delaying the progression of the disease or disorder” (p. 39, lines 14-15), further broadening the scope of the invention to include prevention.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification does not provide any biological assays providing support for the use of Compound B to treat any diseases. A review of the art yields US 12,083,101 (herein Bordas), which teaches Compound B (col. 475, Example 144) and the effectiveness of compound B in inhibiting YAP-dependent transcription in mesothelioma cells and adenocarcinoma cells in vitro. See below rejections under 35 U.S.C. 103 for more explanation of the state of the art. However, the in vitro assays of the effectiveness of Compound B cannot be extrapolated to the treatment in a subject of all diseases mediated by YAP overexpression, YAP amplification, or YAP/TAZ-TEAD interaction, or the treatment of all cancers harboring one or more YAP/TAZ fusions; one or more NF2/LATS1/LATS2 truncating mutations or deletions; or one or more functional YAP/TAZ fusions. As noted above, YAP and the Hippo pathway are implicated in numerous complex pathways in humans, such as interactions with the broader immune system, which cannot be reasonably predicted or determined in an in vitro assay on two cancer cell lines.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that a crystalline form of Compound B could be predictably used to treat all diseases and conditions mediated by YAP overexpression, YAP amplification, and YAP/TAZ-TEAD interaction, or to treat any cancer or tumor harboring one or more YAP/TAZ fusions; one or more NF2/LATS1/LATS2 truncating mutations or deletions; or one or more functional YAP/TAZ fusions, outside of adenocarcinoma and mesothelioma known in the art. Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a 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" (42 USPQ 2d 1001, Fed. Circuit 1997).
As noted above, the specification in view of the prior art provides no experimental support for the treatment of any disease or disorder in which YAP overexpression, YAP amplification, or YAP/TAZ-TEAD interaction is implicated. A review of the state of the art fails to reveal that a crystalline form of Compound B is useful as therapeutic for the treatment of any cancer, disease, or condition within the scope of the instant claims. Determining if any particular claimed compound would treat any particular cancerous disease state would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicants. As noted supra, even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy.
Accordingly, claims 73 and 75 do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
112(b)
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 4, 54, 60, 73, and 75 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.
Claim 4 recites the limitations "the temperature" and “the radiation” following the table of X-ray powder diffraction peaks. There is insufficient antecedent basis for these limitations in the claim. Claims 54 and 60 also recite the limitations “the temperature” and “the radiation” following the table of X-ray powder diffraction peaks, and also have insufficient antecedent basis for these limitations.
Additionally, regarding claims 4, 54, 60, and 75, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 4 recites the broad recitation “characterized by an X-ray powder diffraction pattern comprising peaks at four or more 2θ values[…]selected from”, and the claim also recites “and preferably wherein the X-ray powder diffraction pattern comprises at least the peaks at 13.26° ±0.2°, 16.99° ±0.2°, 19.92° ±0.2° and 26.66° ±0.2°” which is the narrower statement of the range/limitation. Similarly, claim 54 recites the broad recitation “characterized by an X-ray powder diffraction pattern comprising four or more 2θ values[…] selected from”, and the claim also recites “and preferably wherein the X-ray powder diffraction pattern comprises at least the peaks at 7.00° ±0.2°, 9.21° ±0.2°, 10.98° ±0.2° and 21.80° ±0.2°”. Claim 60 recites the broad recitation “characterized by an X-ray powder diffraction pattern comprising four or more 2θ values[…]selected from”, and the claim also recites “and preferably wherein the X-ray powder diffraction pattern comprises at least the peaks at 10.98° ±0.2°, 11.78° ±0.2°, 16.79° ±0.2° and 20.00° ±0.2°”.
Claim 75 recites the broad recitation “’wherein the cancer, tumor, or disease is selected from mesothelioma”, and the claim also recites “including malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and mesothelioma of the tunica vaginalis”. Claim 75 similarly recites numerous generic cancers as broad recitations, followed by “including” species of said cancer (for example, “carcinoma” followed by “including cervical squamous cell carcinoma, endometrial carcinoma,[…] and squamous cell carcinoma of the skin” and “breast cancer” followed by “including triple negative breast cancer”).
The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Furthermore, regarding claims 4, 54, and 60, the phrase "for example”, in abbreviated form as ‘e.g.’: “peaks at four or more 2θ values (e.g. 5 or more, e.g. 6 or more,...)” renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Finally, claim 73 claims both “a method of treating a disease or condition mediated by YAP overexpression[…]” and “a method of treating a cancer or tumor harboring (i) one or more YAP/YAZ fusions[…]”. It is unclear which method is intended in the scope of this claim.
Claim Rejections - 35 USC § 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)(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 and 2 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Bordas (US 12,083,101 B2, filed Mar. 15, 2021).
The applied reference has a common applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Bordas teaches the synthesis of 2-((2S,3S,4S)-5-Chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (col. 475, Example 144). This is the same as instant Compound B. The absolute configuration of Example 144 was confirmed by an X-ray cocrystal structure (col 478, lines 11-12).
Bordas also teaches the synthesis of 4-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxy ethoxy)-N-methylnicotinamide (col. 502, Example 155). This is the same as instant Compound A. The absolute configuration of Example 155 was confirmed by an X-ray cocrystal structure (col. 506, lines 14-15).
Regarding claim 1, the X-ray cocrystal structure of Bordas Example 144 reads on a crystalline form of instant Compound B.
Regarding claim 2, the X-ray cocrystal structure of Bordas Example 155 reads on a crystalline form of instant Compound A.
Therefore, the above reference anticipates the instantly claimed invention.
Claim Rejections - 35 USC § 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.
Claims 1-3, 8 13, 18, 23, 28, 33, 42, 47, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Bordas (US 12,083,101 B2, filed Mar. 15, 2021).
As discussed above (see claim rejections under 35 U.S.C. 102), Bordas teaches an X-ray cocrystal form of Compound A and an X-ray cocrystal form of Compound B. Bordas teaches the purification of Compound A via flash chromatography (col. 506, lines 2-3), as well as the purification of Compound B via the same method (col. 477, lines 39-42). Bordas teaches that purification can also be done via recrystallization techniques. The teachings of Bordas are applied as above, thus rejecting claims 1-2.
Bordas also teaches compounds of their disclosure in benzoate, glutamate, lactate, malate, maleate, malonate, mesylate, and succinate salt form (col. 46, lines 3-17). Bordas further teaches that compounds of the present invention, including their salts, can include other solvents used for their crystallization (col. 47, lines 62-65), as well as pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier (claim 18).
Finally, Bordas teaches the treatment of mesothelioma and adenocarcinoma cells in vitro using Compound B (col. 538, Example 144; cell lines described col. 535, lines 11-15; equivalence of Compound B and Example 144 given above in rejections under 35 USC 102), and teaches the results indicate that compounds may be useful in the treatment of diseases or conditions mediated by YAP overexpression, YAP amplification, or YAP/TAZ-TEAD interaction (col. 538, lines 48-51).
Bordas does not explicitly teach crystalline forms of the above salts. Similarly, Bordas does not explicitly teach crystalline forms of Compounds A and B in free form, a pharmaceutical composition comprising a crystalline form of Compound B, or a method of administering a crystalline form of Compound B.
Regarding claim 3, it would have been obvious to one of ordinary skill in the art before the invention was filed to make a succinate salt of a crystalline form of Compound B. One would have been motivated and had a reasonable expectation of success to do so since Bordas teaches salts of compounds including Compound B can be crystallized and since Bordas teaches a succinate salt form of compounds of formula (Ia).
Regarding claim 8, it would have been obvious to one of ordinary skill in the art before the invention was filed to make a malate salt of a crystalline form of Compound B. One would have been motivated and had a reasonable expectation of success to do so since Bordas teaches salts of compounds including Compound B can be crystallized and since Bordas teaches a malate salt form of compounds of formula (Ia).
Regarding claim 13, it would have been obvious to one of ordinary skill in the art before the invention was filed to make a lactate salt of a crystalline form of Compound B.
Regarding claim 18, it would have been obvious to one of ordinary skill in the art before the invention was filed to make a benzoate salt of a crystalline form of Compound B.
Regarding claim 23, it would have been obvious to one of ordinary skill in the art before the invention was filed to make a glutamate salt of a crystalline form of Compound B.
Regarding claim 28, it would have been obvious to one of ordinary skill in the art before the invention was filed to make a maleate salt of a crystalline form of Compound B. One would have been motivated and had a reasonable expectation of success to do so since Bordas teaches salts of compounds including Compound B can be crystallized and since Bordas teaches a maleate salt form of compounds of formula (Ia).
Regarding claim 33, it would have been obvious to one of ordinary skill in the art before the invention was filed to make a malonate salt of a crystalline form of Compound B. One would have been motivated and had a reasonable expectation of success to do so since Bordas teaches salts of compounds including Compound B can be crystallized and since Bordas teaches a malonate salt form of compounds of formula (Ia).
Regarding claim 42, it would have been obvious to one of ordinary skill in the art before the invention was filed to make a mesylate salt of a crystalline form of Compound B. One would have been motivated and had a reasonable expectation of success to do so since Bordas teaches salts of compounds including Compound B can be crystallized and since Bordas teaches a mesylate salt form of compounds of formula (Ia).
Regarding claim 47, it would have been obvious to make a crystalline form of Compound B in free form because Bordas teaches purification of Compound B via flash chromatography and also teaches compounds of the disclosure can be purified via recrystallization. One would have been motivated and had a reasonable expectation of success to substitute one purification process (flash chromatography) with a different process (recrystallization) since the prior art teaches they function in a similar manner. Recrystallization would yield the free form of Compound B.
Regarding claim 53, it would have been obvious to make a crystalline form of Compound A in free form because Bordas teaches purification of Compound A via flash chromatography and also teaches compounds of the disclosure can be purified via recrystallization. One would have been motivated and had a reasonable expectation of success to substitute one purification process (flash chromatography) with a different process (recrystallization) since the prior art teaches they function in a similar manner. Recrystallization would yield the free form of Compound A.
Taken all together, all this would result in the invention of claims 1-3, 8, 13, 18, 23, 28, 33, 42, 47, and 53 with a reasonable expectation of success.
Claims 69, 73, and 75 are rejected under 35 U.S.C. 103 as being unpatentable over Bordas (US 12,083,101 B2) as applied to claims 1-3, 8 13, 18, 23, 28, 33, 42, 47, and 53 above, and further in view of Censi (Molecules 2015, 20, 18759-18776).
The teachings of Bordas are set forth above. Bordas does not teach the use of crystalline forms of Compound B in pharmaceutical compositions or treatment of diseases.
Censi teaches that many drugs can crystallize into different polymorphic forms, which may improve stability and solubility over the original form of these drugs (pp. 18761-18762, section 3. “The Polymorphism of Drugs: Anhydrous and Solvated Forms”, paras. 2-3). Censi also teaches that polymorphs may help with poor bioavailability of drugs (abstract, lines 1-4).
Regarding claim 69, it would have been obvious to create a pharmaceutical composition of a crystalline form of Compound B. One would have been motivated and had a reasonable expectation of success to do so since Bordas teaches a pharmaceutical composition of non-crystalline forms of compounds of their formula (Ia) including Compound B and also teaches a crystalline form of Compound B, and since Censi teaches crystalline polymorphs may help with bioavailability of drugs. One would have been motivated to use a crystalline form of Compound B in a pharmaceutical composition to help with bioavailability.
Regarding claims 73-75, it would have been obvious to administer a crystalline form of Compound B to treat mesothelioma and adenocarcinoma mediated by YAP overexpression, YAP amplification, or YAP/TAZ-TEAD interaction. One would have been motivated and had a reasonable expectation of success to do so since Bordas teaches Compound B is useful in the treatment mesothelioma and adenocarcinoma and in the treatment of conditions mediated by YAP overexpression, YAP amplification, or YAP/TAZ-TEAD interaction and also teaches a crystalline form of Compound B, and since Censi teaches crystalline polymorphs may help with bioavailability of drugs.
Taken all together, all this would result in the invention of claims 69, 73, and 75, with a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 47, 53, 69, 73, and 75 are rejected on the ground of nonstatutory double patenting as being unpatentable over at least claims 1, 7, 18, and 20-22 of U.S. Patent No. 12,083,101 B2 (herein Bordas) in view of Censi (Molecules 2015, 20, 18759-18776).
Claim 1 of Bordas teaches compounds of formula (Ia). Claim 7 of Bordas teaches Compound A (col. 551, lines 62-64) and Compound B (col. 551, lines 27-29), which are compounds of formula (Ia), and pharmaceutically acceptable salts thereof.
Claim 18 teaches a pharmaceutical composition of compounds of formula (Ia). Claim 20 teaches a method of treating a cancer in a subject comprising administering a compound of formula (Ia). Claim 21 teaches wherein the cancer harbors one or more YAP or TAZ fusions or one or more NF2, LATS1, or LATS2 truncating mutations or deletions. Claim 22 teaches wherein the cancer is mesothelioma, carcinoma, poroma, and other specific cancers.
Claim 7 of Bordas does not teach crystalline forms of compounds A and B. However, Censi teaches that many drugs can crystallize into different polymorphic forms, which may improve stability and solubility over the original form of these drugs (pp. 18761-18762, section 3. “The Polymorphism of Drugs: Anhydrous and Solvated Forms”, paras. 2-3).
Thus, regarding instant claim 1, it would have been obvious to one of ordinary skill in the art to make a crystalline form of Compound B. One would have been motivated and had a reasonable expectation of success to modify the amorphous form taught by Bordas since Censi teaches crystalline forms of drugs may offer improved stability and solubility of these drugs. Likewise, it would have been obvious to make a crystalline form of Compound B in free form, as in claim 47. Similarly, regarding claim 2, it would have been obvious to make a crystalline form of Compound A, and regarding claim 53, it would have been obvious to make a form wherein Compound A is in free form.
Regarding claim 69, it would have been obvious to create a pharmaceutical composition of a crystalline form of Compound B. One would have been motivated and had a reasonable expectation of success to do so since Bordas teaches a pharmaceutical composition of non-crystalline forms of compounds of their formula (Ia) including Compound B and also teaches a crystalline form of Compound B, and since Censi teaches crystalline polymorphs may help with bioavailability of drugs. One would have been motivated to use a crystalline form of Compound B in a pharmaceutical composition to help with bioavailability.
Regarding claim 73, it would have been obvious to administer a crystalline form of Compound B to treat a cancer harboring (i) one or more YAP or TAZ fusions; or (ii) one or more NF2, LATS1, or LATS2 truncating mutations or deletions. One would have been motivated and had a reasonable expectation of success to do so since Bordas claims compounds of their formula (Ia), including Compound B, are useful in the treatment of such cancers and also teaches a crystalline form of Compound B, and since Censi teaches crystalline polymorphs may help with bioavailability of drugs.
Regarding claim 75, it would have been obvious to administer a crystalline form of Compound B to treat a cancer harboring (i) one or more YAP or TAZ fusions; or (ii) one or more NF2, LATS1, or LATS2 truncating mutations or deletions, wherein the cancer is selected from mesothelioma, carcinoma, poroma, and other cancers recited in claim 22 of Bordas. One would have been motivated and had a reasonable expectation of success to do so since Bordas claims compounds of their formula (Ia), including Compound B, are useful in the treatment of cancers harboring (i) one or more YAP or TAZ fusions; or (ii) one or more NF2, LATS1, or LATS2 truncating mutations or deletions, are useful in the treatment of mesothelioma, carcinoma, poroma, and other specific cancers (see claim 22 of Bordas), and also teaches a crystalline form of Compound B, and since Censi teaches crystalline polymorphs may help with bioavailability of drugs.
Taken all together, the claims of Bordas in view of Censi would result in the invention of instant claims 1, 2, 47, 53, 69, 73, and 75 with a reasonable expectation of success.
Conclusion
Claims 1-4, 8, 13, 18, 23, 28, 33, 42, 47, 53-54, 60, 69, 73, and 75 are rejected.
Claims 4, 48, 54, 59, 60, and 75 are objected to.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OLIVER D. HEES whose telephone number is (571)272-9840. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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/O.D.H./Examiner, Art Unit 1628
/Rayna Rodriguez/Primary Examiner, Art Unit 1628
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