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 .
Priority
This application is a 371 of PCT/US2022/016813 (02/17/2022)
PCT/US2022/016813 has PRO 63/151,479 (02/19/2021).
Status
Rejections not reiterated are withdrawn.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-12, in the reply filed on 1/20/26 is acknowledged. The traversal is on the ground(s) that unity of invention exists. This is not found persuasive because as detailed in the following prior art rejection unity of invention does not exist as the feature linking the claims of the compound is not a contribution over the art.
The requirement is still deemed proper and is therefore made FINAL.
Applicant also elected the following species:
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stated as reading on claims 1-3, 5, 7, 9, 10-12.
As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. Therefore, the provisional election of species is given effect, the examination is restricted to the elected species only, and claims not reading on the elected species are held withdrawn. MPEP 803.02; Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (Bd. Pat. App. lnt. 1987). Accordingly, claims 4, 6, 8 are hereby withdrawn.
Should applicant, in response to this rejection of the Markush-type claim, overcome the rejection through amendment, the amended Markush-type claim will be reexamined to the extent necessary to determine patentability of the Markush-type claim. See MPEP 803.02.
Claim Rejections - 35 USC § 103
Claims 1-2, 9, 10, 12 are rejected under 35 U.S.C. 103 as being unpatentable over Labadie et al. (WO2017174757) in view of Patani et al. (Chem. Rev., 1996, Vol. 96, No. 8, p. 3147-3176).
Labadie teaches estrogen receptor alpha (ERa) modulator compounds of Formula (I) (p. 22-23, claim 1) including the following compounds 104 and 116 (Tables 1-2, p. 31-51) showing high levels of ERa activity:
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Compound 104 Corresponding to claim 1’s formula (I) where R1 is H, R2 is H (not methyl), R3 is 2-fluoro-isopropyl (C3-alkyl substituted by halo), X1 and X2 are O, n is 2, R4 is azetidine (C3 heterocycloalkyl), R5 is C1 alkyl substituted by halo. Labadie’s claim 1 genus of formula (I) encompasses instant claim 1.
Thus, compound 104 differs from the scope of claim 1 by R2 is H vs. methyl. Alternatively, compound 116 differs from the scope of claim 1 by -S(O)2- vs. -C(O)-.
One of ordinary skill in the art would have considered modifying Labadie’s compound 104 to incorporate a methyl group as was demonstrated as successful in compound 116. Alternatively, one of ordinary skill in the art would have considered modifying Labadie’s compound 116 to replace S(O)2 with C(O) due to the success of compound 104. One of ordinary skill in the art would have considered such a modification because of the successful experimental demonstration of the compounds as modulators of ERa and because Labadie’s genus teaches the modification as within the scope of ERa modulator compounds. In addition, the level of skill in the art is very high and such modifications are routine in the art as taught by Patani wherein is demonstrated that H and methyl, as well as C(O) and S(O)2 are known as bioisosteres (p. 3152, 3166-67). One of ordinary skill in the art would have had a reasonable expectation of success because of the experimental demonstrations reported by Labadie as well as the well-known bioisosterism relationship.
With each of the claims, the level of skill in the art is very high such that one of ordinary skill in the art would consider routine the combination of elements from the teaching of the art. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known nature and optimizations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed before the effective filing date with a reasonable expectation of success.
Response to Remarks - 35 USC § 103
Applicant argues that the substituent on the nitrogen impacts the activity of Labadie’s compounds such that one of ordinary skill in the art would not have methylated compound 104.
This argument is not persuasive because Labadie’s claim 1 genus encompasses species where a methyl group is at the position in question, the 3-position on the 3,4-dihydro-1H-isoquinolin-2-yl ring. In addition, Labadie teaches a number of example compounds showing very high level of activity with varying substitutions on the nitrogen with a methyl substituent such that one of ordinary skill in the art would have had a reasonable expectation that methylation of the 3-position of compound 104 would result in an active compound. See for example compounds 132, 158, and 166 having EC50 values of 0.000011, 0.000042, and 0.000066, respectively:
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,
while compound 104 showed EC50 of 0.000741 (Table 1a):
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Thus, one of ordinary skill in the art considering the teaching of Labadie as a whole, including the genus of claim 1, the example compounds, and the significant structural similarities (identical except for the 2,3-positions subsitutents) among the above compounds, would have had a reasonable expectation of success in making the substitution on compound 104 and arriving at the claimed invention.
Applicant argues that there were several instances where methylation of the 3-position resulted in a decrease or no change in activity.
This argument is not persuasive at least because one of ordinary skill in the art would have recognized the importance of the 1-position R-stereoisomer (referred to as “C1 configuration” by applicant) on activity as well as the substituent effect. For example, compound 110 methylated would be compound 116 which shows improved EC50 (0.00828 to 0.00030). Thus, C1-R-stereoisomers (which are the same configuration as compound 104, 106, 132, and 158) all show relatively high levels of activity and would have reasonably suggested the same modification to one of ordinary skill in the art.
Applicant also argues regarding the alternative basis of obviousness based on modifying compound 116’s SO2 to CO that one of ordinary skill in the art would not have considered the modification in view of larger improvements in activity achieved by replacing SO2Me with CH2CF3 or CH2CFMe2.
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This argument is not persuasive because, again, as with the argument immediately above, one of ordinary skill in the art would have recognized the importance of the stereoisomer and substitution – for example compounds 104, 106, 110, all show high level of activity through different substitutions at the same position. Thus, there was an expectation of success that the compounds within Labadie’s genus having the same modification would be successful.
Applicant also argues that it is not clear from Labadie if the improvement from compound 110 to 104 arises from replacing SO2 with CO or due to fluoroalkyl groups.
This argument is not persuasive because one of ordinary skill in the art would have recognized that such modifications could both or alternatively improve the compounds activity and would have screened them with a reasonable expectation of success. See MPEP 2143.02: Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) (“To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’”); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) (“This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness.” (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that “the expectation of success need only be reasonable, not absolute”)).
Claim Objections
Claims 3, 5, 7, 11 are objected to for being dependent on a rejected base claim and reading on non-elected subject matter as a result of the restriction to the elected species ONLY.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. 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 ROBERT H HAVLIN whose telephone number is (571)272-9066. The examiner can normally be reached 9am - 6pm.
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/ROBERT H HAVLIN/Primary Patent Examiner, Art Unit 1626
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