DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1, 3, 6-12 are pending and examined here.
Priority
The benefit of US Application 15/962,894, filed on 04/25/2018, is recognized. All claims enjoy the filing date of ‘894.
Claim Rejections - 35 USC § 103
Rejection of claims 1, 3, 6-8 is maintained and new claims are rejected as noted below.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 6-12 are rejected under 35 U.S.C. 103 as being unpatentable over Devergnas et al. (2016, J. Neurophysiol., 115, 470-485) in view of Kim et al. (US20130184321, pub. 07/18/2013, referred as Kim; the inventors are co-inventors with instant app., but the publication is prior to the 102(b)(2) exception period).
Regarding instant cl. 1, 3, and 6-9, SEQ ID NO: 4 is the following:
cggaattccg ggaagatcgt agatagcaaa ttcaagagat ttgctatcta cgatcttctt tttgatatct agaca, a 75 nt. shRNA sequence.
Devergnas et al. disclose that a prominent Parkinson-related event is abnormal, neuronal burst discharges in, amongst other region, motor thalamus region, which is at least partially due to the fact that they strongly express T-type calcium channels (pg. 470). Thus, Devergnas disclose treatment with ML218, a T-type calcium channel blocker, to eliminate the pathologic burst patterns of firing in the basal ganglia-receiving territory of the motor thalamus in monkeys treated with MPTP, a drug to mimic Parkinson’s disease (Abstract). Immunostaining with Cav3.1 T-type calcium channel antibody demonstrated the localization of the immunostaining in the basal ganglia-receiving territory of the treatment drug (pg. 475). The treatment partially normalized the thalamic activity by reducing the proportion of rebound bursts and increasing the proportion of spikes in non-rebound bursts (Abstract). Devergnas indicates that there is a “continuing need to develop nondopaminergic approaches to treat Parkinsonism” due to complications caused by dopamine replacement therapy (abstract).
Devergnas does not disclose the shRNA inhibitor, SEQ ID NO: 4, nor a lentivirus vector.
Kim discloses the shRNA inhibitor SEQ. ID. NO: 1 (5′-CGGAATTCCGGGAAGATCGTAGATA GCAAAttcaagagaTTTGCTATCTACGATCTTCTTTTTGATATCTAGACA-3′), which is 100% identical to instant SEQ ID NO: 4, and targets “Cav3.1 T-type calcium channel” to inhibit the expression of the Cav3.1 transcript (par. 191, Kim uses Cav3.1 and α1G interchangeably, see claim 10; relevant to instant cl. 1, 3, 9); discloses the insertion of the shRNA SEQ ID NO: 1 into a lentivirus vector (par. 191, relevant to instant cl. 6, 7, 8). Further Kim discloses reduction in abnormal electroencephalogram spikes in the ADHD mouse (see Fig. 7A) and a “huge decrease of brain waves with low frequency in the animal model” (see Fig. 7B) following administration of shRNA of SEQ ID NO: 1.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is 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. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have substituted ML218, a type of T-type calcium channel blocker/inhibitor, for treating pathologic firing in Parkinson’s disease subject of Devergnas with the shRNA targeting a specific type of T-type calcium channel inhibitor of Kim and arrive at the claimed invention with a reasonable expectation of success. Based on Devergnas observation of treating Parkinsonian monkeys with ML218, an inhibitor of T-type Ca2+ channel blocker, to reduce pathologic neuronal firings, and Kim’s observation that SEQ ID NO: 1 inhibits expression of CaV3.1 channel, a skilled artisan would expect reasonable success in treating Parkinsonian monkeys by administering SEQ ID NO: 1 of Kim to reduce the expression/activity of CaV3.1 T-type calcium channel in aforementioned sub-thalamic region to reduce pathologic neuronal firings in Parkinsonian monkeys.
Regarding claims 10-12, the results noted in claims 10-12 (reduction in tremors, muscle rigidity, motor abnormality) would be the inherent results of administration of SEQ ID NO: 1 of Kim, which is 100% identical to instant SEQ ID NO: 4, unless the Applicant can provide evidence noting otherwise. Thus, claims 10-12 are obvious.
Response to Arguments
Applicant's arguments filed 9/15/2025 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks raise similar issues as prior action and its response re-copied here and also adds that Devergnas is silent concerning ML218’s IC50 data relative to its inhibition of the specific Cav3.1 and thus concludes “potency of ML218 on Cav3.1 is unclear” (pg. 5) and the Kim reference is concerning ADHD and does not disclose Parkinson’s disease and the shRNA is administered to a different locus in the brain (i.e. MD thalamus) (pg. 5); and further note that behavioral data are unexpected.
The Remarks note that “given the diffusive nature, non-specific action, and unknown Cav3.1 potency of ML218, the precise location where ML218 exerts its effect, and the precise target through which the desirable effect is generated are entirely unclear from the disclosure of Devergnas” (pg. 5).
The argument is not persuasive.
Regarding the “non-specific” ML-218 effects, it does not change the fact that ML218 still inhibited Cav3.1 containing neurons and therefore its inhibition still played a prominent role in inhibition of rebound firing, as noted above. It would be prima facie obvious to substitute the Cav3.1 shRNA for the broader spectrum inhibitor ML218. Thus it is reasonable for one skilled in the art to inhibit the activity of T-type calcium channels, both by blockers and shRNA that target any such 3-types of T-type calcium channels to evaluate its effects.
Regarding the “diffusive” argument), Devergnas counters by noting that “because ML218 effects were found, regardless of the distance of the microinjections to the reticular nucleus (see Fig. 4), we believe that most of the changes described in our study were due to local drug effects in the basal ganglia-receiving territory of the thalamus” (pg. 483);
Regarding the lack of IC50 data, the full quote regarding IC50 by Devergnas counters this argument: “However, the concentration of ML218 used in our study (2.5 mM) was high compared with its effective concentrations at Cav3.3 and Cav3.2 channels found in in vitro electrophysiology [IC50 of 270 and 310 nM, respectively (Xiang et al. 2011)], making us confident that a very large proportion of the T-type calcium channels were, in fact, blocked. Further confirmation comes from the fact that we saw, as expected, a reversal of many Parkinsonism-associated changes in parameters describing burst behaviors” (pg. 483). Thus inhibition can be monitored by different methods that is recognized in the art, and here, IC50 is provided for similar T-type calcium channels and Devergnas uses other markers for inhibition.
Regarding the silence of Devergnas to behavioral changes: The purpose of Devergnas study was to study the cellular and subcellular distribution of Cav3.1 and characterize the electrophysiological effects of local microinjections of ML218 on neurons in the basal ganglia-receiving area of the ventral motor thalamus in Parkinsonian monkeys (pg. 471, underline added for emphasis). Further the local ML218 injections were administered for a short time period (minutes) to understand the changes in neuronal electrophysiology behavior (see Microinjections and recordings in Methods, pg. 473, and pg. 474). Thus, a skilled artisan would not expect to see alleviation of Parkinson’s behavioral symptoms within minutes (or arguably hours). Further, here, the MPTP treatment also resulted in “a significant loss of TH immunoreactivity” throughout the caudate nucleus, the putamen and substantia nigra (SN) (pg. 474, Fig. 1), thus this neuronal loss would not be cured by treating with ML218.
Regarding Kim does not even concern Parkinson’s disease, In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The obviousness is that Devergnas teaches inhibition of Cav3.1 channels results in inhibition of rebound firings in a specific thalamus region and Kim is used to provide for a different yet specific shRNA inhibitor of Cav3.1 that has been applied in vivo.
Regarding the Fig. 17 noted in Remarks, reduction of tremors and akinesia in knock-out of Cav3.1 animal, the results are expected and would be obvious. The knock-out animal is an alternative manner in studying effects of complete removal of a gene, as opposed to knock-down of a target gene, which reduces the level of the target protein, but may still have residual expression of the target protein. The knock-out animal is similar to, as the Remarks argue, administering a “higher dose than the already established effective dose” so as to get complete inhibition of the T-type calcium channels, which is what was done by Devergnas.
Regarding Fig. 29C, regarding reduction in tremors, the claimed subject matter requires treatment with SEQ ID NO: 4 to a subject at a particular location, and obviousness rejection noted above satisfies the limitation and one of the result of the administration of the shRNA is reduction in tremors. Further, inhibition of T-type calcium channels to treat PD symptoms is known. Yang et al. (2014, Pflugers Archiv.-Eur J. Physiol., 466, 747-755) titles their review “The T-type calcium channel as a new therapeutic target for Parkinson’s disease” and discloses that “[l]ocal application of T-type Ca2+ channel blockers into STN [subthalamic nucleus] would also dramatically decrease the burst discharges and improve parkinsonian locomotor symptoms. Notably, zonisamide, which could inhibit T-type Ca2+ currents in STN, has been shown to benefit PD patients in a clinical trial” (abstract). Thus, Yang discloses improvement of Parkinson locomotor symptoms by inhibiting T-type Ca2+ channel. Although Yang is not specific regarding the T-type calcium channel, based on studies of Devergnas, a skilled artisan would specifically target inhibition of Cav3.1. Thus, treatment with Cav3.1 shRNA resulting in decrease of tremors would not be unexpected.
Here, treatment with shRNA targeting Cav3.1 merely amounts to new and nonobvious uses of an old structure by discovery of unappreciated properties of a prior art product (see MPEP 2112(I)).
Thus the rejection of examined claims is maintained.
Conclusion
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 KEYUR A. VYAS whose telephone number is (571)272-0924. The examiner can normally be reached M-F 9am - 4 pm (EST).
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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600