DETAILED ACTION
Status of Application
The response filed 11/12/2025 has been received, entered and carefully considered. The response affects the instant application accordingly:
Claims 1-3 have been amended.
Claims 4-6 has been cancelled.
Claims 1-3, 7-26 are pending.
Claims 1-3, 7-26 are present for examination at this time.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All grounds not addressed in the action are withdrawn or moot as a result of amendment.
New grounds of rejection are set forth in the current office action as a result of amendment.
New Grounds of Rejection
Due to the amendment of the claims the new grounds of rejection are applied:
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, 7-25 are rejected under 35 U.S.C. 103 as being unpatentable over Zarnitsyn et al. (U.S. Pat. Pub. 2016/0213662).
Rejection:
Zarnitsyn et al. teaches treating posterior/choroidal eye conditions with the non-surgical administration of a drug like axitinib (PDGF antagonist) to the suprachoroidal space (SCS) of the eye (claim 1). The eye condition is neovascular age related macular degeneration (AMD [8]) and a choroidal malady like choroidal neovascularization (neovascularization of the choroid, CNV) including CNV secondary to wet/neovascular AMD (claims 1-5, 7-8, [9, 16, 103, 107, 144, 149, 153, 179-180, 189, 191, 295]). The amount of drug can be about 0.05mg-about 5mg [133]. The volume for the formulation administered to the suprachoroidal space is from about 10 μL to about 200 μL [119]. The drug is released for an extended period (sustained release) e.g. months after administration and can provide increase bioavailability compared to other means like topical [67, 131]. The therapeutic efficacy of the formulation can be assessed by measuring changes like visual acuity and retinal thickness [134-135, 277, 295-296]. These change can be done with monitoring can be done with ocular coherence tomography like spectral domain optical coherence tomograph [125, 135, 277] The treatment can have an additional active such as a VEGF antagonist like bevacizumab (Avastin®) or ranibizumab (Lucentis®) or pegaptanib sodium (Macugen®, [11,17, 163, 178]) which are known for AMD that can be in the same or separate formulation and administered intravitreally ([213-214], see full document specifically areas cited).
While Zarnitsyn et al. does not teach the exact claimed range of axitinib, it does overlap (about 0.05mg-about 5mg embraces values like 0.05, 0.1, 0.5, 1 and 2mg which fall in the instantly claimed range of about 0.01-about 2mg), wherein even a slight overlap in ranges establishes a prima facie case of obviousness as it is obvious before the effective filing date of the claimed invention to optimize within the taught range to attain the desired therapeutic profile and arrive at the overlapping values absent evidence of criticality of the claimed range. As the same active is administered in the same manner for the same condition with the overlapping values, the decrease (and no increase) in retinal thickness and minimal/no loss in vision and improvement of vision (visual acuity (BCVA), gain of letters) compared to before treatment would be expected to be the same as instantly claims as the specification addresses that the administration of the axitinib in this manner for the eye condition would result in these effects.
While Zarnitsyn et al. does not recite the exact claimed concentration of about 1mg/ml axitinib, it does embrace it as the axitinib is about 0.05mg-about 5mg and the volume for the formulation administered to the suprachoroidal space is from about 10 μL to about 200 μL; wherein the concentration is about 0.25mg/ml-500mg/ml (0.05mg/200ul=0.05mg/0.2ml=0.25mg/ml, 5mg/10ul=500mg/ml) and it is prima facie obvious before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed value as a means to attain the desired therapeutic profile absent evidence of criticality for the claimed concentration.
Zarnitsyn et al. does not expressly teach giving a second dose of axitinib at least 2 months or more after the first dose but does expressly teach treating of eye conditions like wet AMD with the administration of axitinib to the suprachoroidal space of the eye (claim 1) and that there is sustained release of the drug for an extended period such as months after administration (i.e. after 2 months, after 6 months) wherein it would be prima facie obvious before the effective filing date of the claimed invention to give another dose the axitinib (second dose) to the patient after the formulation is done releasing the drug to provide continued treatment which is desirable with a reasonable expectation of success.
Response to Arguments:
Applicant's arguments centered on the assertion that the prior art is limited to preclinical animal experiments and lacks any disclosure or demonstration of human use, that one would not have been motivated to combine teachings of the references without hindsight, that there is not a reasonable expectation of success for axitinib could be safely administered via the suprachoroidal space at the claimed dose, and the assertion of unexpected results descried in Example 5 in humans with suprachoroidal injection of CLS-AX at 0.03, 0.1, 0.5, and 1mg in 100uL doses over three months with no serious adverse events and treatment emergent adverse events observed and sustained statistically significant long term therapeutic benefits.
This is fully considered but not persuasive.
Contrary to Applicant’s assertion that there is no disclosure for human use (i.e. safety/efficacy or dosing parameter), the prior art of Zarnitsyn et al. explicitly teaches and claims the method of treating humans with nonsurgical administration of axitinib to the suprachoroidal space of the eye to treat eye conditions like macular degeneration (claim 1-2) with a specific dosage range as addressed above wherein the argument is not persuasive. The argument of hindsight for the combination of references is not persuasive as the obviousness rejection is to a single reference and not to a combination as alleged by Applicant, and as the amount of axitinib administered to the suprachoroidal space overlaps the taught range - even a slight overlap in ranges establishes a prima facie case of obviousness as it is obvious before the effective filing date of the claimed invention to optimize within the taught range to attain the desired therapeutic profile and arrive at the overlapping values absent evidence of criticality of the claimed range. Applicant asserts unexpected results are described in Example 5 in humans with suprachoroidal injection of CLS-AX at 0.03, 0.1, 0.5, and 1mg in 100uL doses over three months with no serious adverse events and treatment emergent adverse events observed and sustained statistically significant long term therapeutic benefits, this is fully considered but not persuasive. Example 5 of the specification is a prophetic example – it provides a guideline but did not perform the study and the values proposed do not correspond to those asserted by Applicant and there is no data present to support Applicant’s assertion of unexpected result or data within the claimed range and outside the claimed range to establish criticality of the dose range instantly claimed.
Accordingly, the rejection stands.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Zarnitsyn et al. (U.S. Pat. Pub. 2016/0213662) as applied to claims 1-3, 7-25 above, in view of Patel (WO 2017/120600).
The teachings of Zarnitsyn et al. are addressed above.
Zarnitsyn et al. does not expressly teach the claimed components for the formulation for administration but does teach the administration of axitinib and the inclusion of excipients for the formulation [207].
Patel teaches that axitinib is known to be formulation for the eye for administration to the suprachoroidal space with various excipients with embodiment containing polysorbate 80 from about 0.05-about 0.1%w/v including about 0.05%, sodium phosphate monobasic about 0.04-about 0.07%w/v including about 0.059% (embraced by about 0.06%), 0.05-about 0.09%w/v sodium phosphate dibasic including about 0.079% (embraced by about 0.08%), about 0.5-about 1.0%w/v sodium chloride including about 0.79%, about 0.25-about 0.75%w/v carboxymethylcellulose sodium including about 0.5% [19].
Wherein it would be obvious before the effective filing date of the claimed invention to have the axitinib in an ophthalmic formulation with polysorbate 80, sodium CMC, sodium chloride, sodium phosphate monobasic and sodium phosphate dibasic as suggested by Patel and produce the claimed invention; as it is prima facie obvious to have the axitinib in its known ophthalmic formulation that is established to be compatible with the eye for the same purpose (suprachoroidal space) with a reasonable expectation of success.
Response to Arguments:
Applicant's arguments are those to Zarnitsyn which is addressed above.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The teachings of Zarnitsyn are addressed above and Patel is presented merely to demonstrate known formulations of axitinib for administration to the suprachoroidal space wherein it is prima facie obvious to have the axitinib in its known ophthalmic formulation that is established to be compatible with the eye for the same purpose (suprachoroidal space) with a reasonable expectation of success.
Accordingly, the rejection stands.
Claims 1-3, 7-26 are rejected under 35 U.S.C. 103 as being unpatentable over Patel (WO 2017/120600) in view of Zarnitsyn et al. (U.S. Pat. Pub. 2016/0213662).
Rejection:
Patel teaches treating neovascular age related macular degeneration (AMD) and choroidal neovascularization with the administration of axitinib to the suprachoroidal space (SCS) of the eye (abstract, claims 1-4, [4-6]). The treatment can have an additional active that is a VEGF antagonist like bevacizumab (Avastin®) or ranibizumab (Lucentis®) or pegaptanib sodium (Macugen®) and administered intravitreally (claims 6-12).Patel teaches the patient to have a decrease in retinal thickness in the treated eye measured by optical coherence tomography (OCT) compared to the patient's retinal thickness prior to treatment (i.e. ≥25µm, ≥5%, claims 14-18) and maintains/improves vision as measured by best-corrected visual acuity (BCVA, i.e. losing fewer letters, gaining ≥5 letters (no loss), visual acuity), compared to the patient's BCVA measurement prior to treatment (claims 19-20, same as no treatment i.e. a formulation without an active/axitinib). The optical coherence tomography (OCT can be spectral domain optical coherence tomography [133]. That axitinib is known to be formulation for the eye for administration to the suprachoroidal space with various excipients with embodiment containing polysorbate 80 from about 0.05-about 0.1%w/v including about 0.05%, sodium phosphate monobasic about 0.04-about 0.07%w/v including about 0.059% (embraced by about 0.06%), 0.05-about 0.09%w/v sodium phosphate dibasic including about 0.079% (embraced by about 0.08%), about 0.5-about 1.0%w/v sodium chloride including about 0.79%, about 0.25-about 0.75%w/v carboxymethylcellulose sodium including about 0.5% [19]. That the volume of the dose administered can be from about 10μL-about 200 μL [73]. The decrease in retinal thickness can be sustained for various time periods including at least about 2 months or at least about 6 months after each dosing session (giving the next dose i.e. second dose, after at least 2 months, after at least 6 months from the previous dose [134], see full document specifically areas cited).
Patel does not expressly teach the amount of axitinib but does teach administering the axitinib to the suprachoroidal space for treating wet AMD and choroidal neovascularization and a volume of about 10μL-about 200 μL.
Zarnitsyn et al. teaches treating neovascular age related macular degeneration and choroidal neovascularization with the administration of axitinib to the suprachoroidal space (SCS) of the eye (claims 1-5). The amount of drug can be about 0.05mg-about 5mg [133]. The volume for the formulation administered to the suprachoroidal space is from about 10 μL to about 200 μL [119].
Wherein it would be obvious before the effective filing date of the claimed invention to utilize the known range for axitinib for administration to the suprachoroidal space for neovascular AMD as suggested by Zarnitsyn et al. and produce the claimed invention; as it is prima facie obvious to incorporate the axitinib in its known and useful amount for wet macular degeneration and choroidal neovascularization for administration to the suprachoroidal space (SCS) and optimize within the range which overlaps the instant claimed range (about 0.05mg-about 5mg embraces values like 0.05, 0.1, 0.5, 1 and 2mg which fall in the instantly claimed range of about 0.01-about 2mg), wherein even a slight overlap in ranges establishes a prima facie case of obviousness as it is obvious to optimize within the taught range to attain the desired therapeutic profile and arrive at the overlapping values absent evidence of criticality of the claimed range. While Patel in view of Zarnitsyn et al does not recite exact claimed concentration for axitinib, it does embrace it as the axitinib is about 0.05mg-about 5mg and the volume for the formulation administered to the suprachoroidal space for Patel and Zarnitsyn et al. is from about 10 μL to about 200 μL; wherein the concentration is about 0.25mg/ml-500mg/ml (0.05mg/200ul=0.05mg/0.2ml=0.25mg/ml, 5mg/10ul=500mg/ml) and it is prima facie obvious before the effective filing date of the claimed invention to optimize within the taught range and arrive at the claimed value as a means to attain the desired therapeutic profile absent evidence of criticality for the claimed concentration.
Response to Arguments:
Applicant's arguments centered on the assertion that the prior art is limited to preclinical animal experiments and lacks any disclosure or demonstration of human use, that one would not have been motivated to combine teachings of the references without hindsight, that there is not a reasonable expectation of success for axitinib could be safe administered via the suprachoroidal space at the claimed dose, and the assertion of unexpected results descried in Example 5 in humans with suprachoroidal injection of CLS-AX at 0.03, 0.1, 0.5, and 1mg in 100uL doses over three months with no serious adverse events and treatment emergent adverse events observed and sustained statistically significant long term therapeutic benefits.
This is fully considered but not persuasive.
Contrary to Applicant’s assertion that there is no disclosure for human use (i.e. safety/efficacy), the prior art of Patel et al. explicitly teaches and claims the method of treating humans with nonsurgical administration of axitinib to the suprachoroidal space of the eye to treat eye conditions like macular degeneration (claim 1 [18]) where Patel explicitly teaches the method for treating humans wherein it is implicit that it is safe/efficacious for treatment in humans wherein the argument is not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, it is prima facie obvious to incorporate the axitinib in its known and useful amount for wet macular degeneration and choroidal neovascularization for administration to the suprachoroidal space (SCS) as established by Zarnitsyn et al. and optimize within the range which overlaps the instant claimed range - as even a slight overlap in ranges establishes a prima facie case of obviousness to attain the desired therapeutic profile and arrive at the overlapping values absent evidence of criticality of the claimed range. Applicant asserts unexpected results are described in Example 5 in humans with suprachoroidal injection of CLS-AX at 0.03, 0.1, 0.5, and 1mg in 100uL doses over three months with no serious adverse events and treatment emergent adverse events observed and sustained statistically significant long term therapeutic benefits, this is fully considered but not persuasive. Example 5 of the specification is a prophetic example – it provides a guideline but did not perform the study and the values proposed do not correspond to those asserted by Applicant and there is no data present to support Applicant’s assertion of unexpected result or data within the claimed range and outside the claimed range to establish criticality of the dose range instantly claimed.
Accordingly, the rejection stands.
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 1-3, 7-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-9, 11-17, 19, 22-32 of copending Application No. 18776683 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are directed to the same method of treatment with the same active of axitinib and the same mode of administration, the amount of axitinib in the copending claims fall within the instant range which establishes a prima facie case of obviousness. With regards to the amount of polysorbate in the copending claim, it embraces the instant claimed amount wherein it would be prima facie obvious to optimize within the copending claimed range and arrive at the instant claimed value as a means of attaining the desired therapeutic profile absent evidence of criticality for the claimed amount.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments:
Applicant requests that the rejection be held in abeyance.
There are no arguments.
Accordingly, the rejection stands.
Conclusion
Claims 1-3, 7-26 are rejected.
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 GIGI GEORGIANA HUANG whose telephone number is (571)272-9073. The examiner can normally be reached Monday-Thursday 9:00-5:00pm.
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/GIGI G HUANG/Primary Examiner, Art Unit 1613