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 has PRO 63/289,176 (12/14/2021).
Status
Claims 1-13, 15-17 are pending.
Claim rejections not reiterated in this action are withdrawn.
New 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.
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.
Claims 1-11, 16 are rejected under 35 U.S.C. 103 as being unpatentable over Endo et al. (Computational Toxicology 12 (2019) 100095, 10 pages) and Fodor et al. (ACS Chem. Biol. 2018, 13, p. 647−656, SI 1-25) in view of Sivakumar et al. (“Prospects of multitarget drug designing strategies by linking molecular docking and molecular dynamics to explore the protein–ligand recognition process.” Drug Dev Res. 2020;81:685–699.) in view of Yang et al. (US20190183860, published 2019-06-20).
Endo teaches in silico screening of ATG4B inhibitors that interact with the active site (Abstract, Table 1, p. 4-5, Fig. 3). Endo suggests combinations but does not specifically teach combining the two drugs to provide a synergistic or additive effect (p. 9: “[in] chemotherapy, it would be valuable to investigate whether the combination treatment of the present Atg4B inhibitors, 1 and 17, exerts overcoming effects on resistance”).
Fodor teaches screening strategies identified a first and second small molecule allosteric combination, that has multiple targets (Abstract). Fodor modeled a first and second drug in a corresponding first and second binding site showing contact interactions in 3D (Figs. 1-8, SI 17). Fodor administered the combination and measured cell viability assays which showed an additive effect (p. 651-652, Fig 6). Thus, the claims are anticipated.
Regarding claim 2, Fodor teaches allosteric sites (abstract).
Regarding claim 3, Fodor teaches small molecules (abstract).
Regarding claim 4-5, Fodor teaches selecting hits, including small molecules, from screening data (abstract, Fig 3 compound library).
Regarding claim 6, Fodor teaches screening paradigm (p. 649, Fig 3).
Regarding claim 7, Fodor teaches docking (p. 649, Fig 3-4).
Regarding claim 8, Fodor teaches determining atomic displacement (p. 652-53).
Regarding claim 10-11, Fodor teaches normalized ranking (p. 649, Fig 3).
Regarding claim 16, Fodor teaches measuring cell viability assay (Fig. 6, 8).
Sivakumar teaches a method of using docking and molecular dynamics to search for effective drugs and drug cocktails based on interactions with pharmacophores/target-sites as depicted Figure 1 shown below:
PNG
media_image1.png
1246
759
media_image1.png
Greyscale
Sivakumar teaches the use of Autodock in docking the drugs molecules (p. 690-694).
One of ordinary skill in the art following the teaching of Endo and Fodor in view of Sivakumar would have considered applying the same technique to a drug combination to achieve greater therapeutic effect.
One of ordinary skill in the art would have also considered Yang in the same field of endeavor of cancer therapeutics which teaches treating breast cancer by administering tioconazole with a second chemotherapeutic agent, including vinorelbine (Claims 1, 3, 4; [0007]-[0008]); tioconazole has sensitizes / synergizes when combined with a second chemotherapeutic drug ([0110]-[0113]); and teaches in silico screening of FDA-approved drugs using a docking, MD simulations, and Autodock which were also ranked by binding-interaction energy ([0054]-[0055]).
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 in the same field of endeavor. 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 with a reasonable expectation of success.
Claims 12 is rejected under 35 U.S.C. 103 as being unpatentable over Endo et al. (Computational Toxicology 12 (2019) 100095, 10 pages) and Fodor et al. (ACS Chem. Biol. 2018, 13, p. 647−656, SI 1-25) in view of Sivakumar et al. (“Prospects of multitarget drug designing strategies by linking molecular docking and molecular dynamics to explore the protein–ligand recognition process.” Drug Dev Res. 2020;81:685–699.) and Yang et al. (US20190183860, published 2019-06-20) as applied to claims 1-11, 16 above and further in view of Belew et al. (J. Chem. Inf. Model. 2016, 56, 1597−1607).
Regarding claim 12, Fodor teaches ranking by screening paradigm (p. 648-649) and Sivakumar teaches determining from energies of atomic contacts (Figs. 1, p. 689), but does not specifically teach “logarithm of odds scoring”.
Belew teaches analysis of ligand docking and classification / scoring of actives (Title, Abstract) through use of numerical calculations including “log odds” (p. 1601).
One of ordinary skill in the art following the teaching of Endo, Fodor and Sivakumar would have considered using known numerical calculations shown to be useful in scoring interactions among ligand-drug targets as taught by Belew. One of ordinary skill in the art would have considered using such a known technique to improve scoring and arrive at the claimed invention with a reasonable expectation of success based on Belew’s teaching in the same field of endeavor.
New Claim Rejections - 35 USC § 103 – Yang in view of Heudel and Liu
Claims 13-15, 17 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. (US20190183860, published 2019-06-20) in view of Heudel et al. (Anticancer Research July 2020, 40 (7) 3905-3913, Published July 3, 2020) and Liu et al. (J. of Cancer, 2020, 11(19): 5802-5811).
Regarding claims 13-15, Yang teaches treating breast cancer by administering tioconazole with a second chemotherapeutic agent, including vinorelbine (Claims 1, 3, 4; [0007]-[0008]). Yang teaches tioconazole sensitizes / synergizes when combined with a second chemotherapeutic drug ([0110]-[0113]) Yang also teaches in silico screening of FDA-approved drugs using a docking, MD simulations, and Autodock which were also ranked by binding-interaction energy ([0054]-[0055]).
Yang does not teach the specific embodiment of a combination of moxidectin with vinorelbine.
Heudel teaches the successful treatment of breast cancer with viorelbine (Title, Abstract) and in combination with other chemotherapies (p. 3910-11).
Liu teaches moxidectin (MOX) for the treatment of cancers and in combination with other anti-cancer therapies (p. 5809-5810; Figs. 4-6).
One of ordinary skill in the art following the teaching of Yang would reasonably consider the teaching of Heudel and Liu in the same field of endeavor and know that combinations of such anticancer compounds are effective. One of ordinary skill in the art would consider routine and well within their technical grasp the process of combining anti-cancer therapies as suggested by the prior art. In addition, those of ordinary skill in the art would first look to successful therapies already known in the art. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 126 USPQ 186 (CCPA 1960) (the “joint use [of magnesium oxide and calcium carbide] is not patentable” where the prior art teaches “that both magnesium oxide and calcium carbide, individually, promote the formation of a nodular structure in cast iron, and it would be natural to suppose that, in combination, they would produce the same effect and would supplement each other”); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
See also Merck & Co., Inc. v. Biocraft Labs, Inc., 874 F.2d 804, 808 (Fed. Cir. 1989) (“Given the prior art teaching that both amiloride and hydrochlorothiazide are natriuretic, it is to be expected that their coadministration would induce more sodium excretion than would either diuretic alone”); In re Diamond, 360 F.2d 214, 217 (CCPA 1966) (where the evidence showed that synergy was expected because combined drugs targeted different cellular mechanisms, and no evidence to the contrary was produced, “[w]e are not convinced of [the] non-obviousness of the combination of two drugs, A5MP and a glucocorticoid . . . particularly since Appeal the record supports the [PTO’s] contention that the drugs selected are two of the commonly used drugs in the treatment of such collagen diseases”).
In this case, the prior art teaches the vinorelbine and ponatinib are individually effective for treating breast cancer and also suggests their combination with another chemotherapeutic. Therefore, the combination of the two compounds for the very same purpose is prima facie obvious. “[T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 205 USPQ 1069, 1072 (CCPA 1980).
Because combining the two anticancer therapies is taught by the prior art and such combinations have been shown to be successful, one of ordinary skill in the art would have a reasonable expectation of success in arriving at the combination as in the claimed invention.
Regarding new claim 17, as with claim 13 Yang and Heudel combined teach the method and further Yang teaches the activity is measured by a method of in silico drug screening ([0054]-[0055]) which one of ordinary skill in the art would have considered and arrived at the claimed invention with a reasonable expectation of success.
New Double Patenting
Claims 1-13, 15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 10583123 (sharing the same disclosure as Yang et al. US20190183860 in the above rejections) in view of Endo et al. (Computational Toxicology 12 (2019) 100095, 10 pages) and Fodor et al. (BMC Medical Genomics 2015, 8(Suppl 4):S4, pages 1-23 and S1-32), Sivakumar et al. (“Prospects of multitarget drug designing strategies by linking molecular docking and molecular dynamics to explore the protein–ligand recognition process.” Drug Dev Res. 2020;81:685–699.), Belew et al. (J. Chem. Inf. Model. 2016, 56, 1597−1607), and Heudel et al. (Anticancer Research July 2020, 40 (7) 3905-3913, Published July 3, 2020). Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims a method of treating cancer with a combination of tioconazole with a second chemotherapeutic and as with the above prior art rejections renders the instant claims obvious.
Response to remarks
Applicant argues regarding rejections that were withdrawn in favor of the above new grounds of rejection in view of the claim amendments, rendering the argument moot.
Applicant requests the double patenting rejections be held in abeyance. Thus, the rejections are maintained as amended above.
Conclusion
No claims 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 ROBERT H HAVLIN whose telephone number is (571)272-9066. The examiner can normally be reached 9am - 6pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney Klinkel can be reached at (571) 270-5293. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ROBERT H HAVLIN/Primary Patent Examiner, Art Unit 1626
