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 .
The rejection under section 112(b) is withdrawn in view of the amendments in connection with this ground of rejection.
The rejections under section 103 are withdrawn in favor of the following new grouns of rejection, adding Stengel et al., further establishing that Cdc42 is overexpressed in non-small cell lung cancer, colorectal adenocarcinoma, melanoma, breast cancer, and testicular cancer. Elevated levels of the protein have been correlated with negative patient survival. Cdc42 has also been shown to be required for both G1-S phase progression and mitosis, and it also modulates the transcription factors SRF, STAT3, and NFkB; and Qadir “Cdc42, an evolutionary member of Rho GTPase family, is responsible for switching on variety of cellular responses such as cell polarity, cytoskeleton remolding, proliferation, migration, cellular transformation, filopodia and invadopodia formation, invasion, enzyme activity, adhesion membrane trafficking, and transportation. Deregulation of Cdc42 may lead to the development of oncogenic condition. Therefore, it can be concluded that inhibiting the overexpression of Cdc42, cancer progression can be controlled. Hence, deeper knowledge about the mechanism of cancer progression involving Cdc42 can lead to a new era for the development of Cdc42 inhibitors in favor of cancer management at molecular level.”
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, 11, 15, 18, 55, 62, 64-66, 68, 70, 73, 75, 76, 78, 79-81 are rejected under 35 U.S.C. 103 as being unpatentable over: Zheng, et al., 2011, Cellular Signalling. 23 (9) (Zheng); or 1415–23; Ye et al., 2015, International Journal of Oncology (Ye); 46 (2): 757–63; and Zins et al., 2013, Journal of Translational Medicine, 11: 295 (Zins); Stengel et al., Cellular Signalling, 2011, 23 (9): 1415–23, newly cited (Stengel), or Qadir et al., 2015, Biol Drug Des, 86: 432-439, newly cited (Qadir).
in view of:
U.S. Publication No. 20110020274 based on an application by Zheng (Zheng II); and
Cdc42 has been shown to actively assist in cancer progression. Several studies have established the basis for this and hypothesized about the underlying mechanisms:
Zheng teaches that Cdc42 is overexpressed in non-small cell lung cancer, colorectal adenocarcinoma, melanoma, breast cancer, and testicular cancer. Elevated levels of the protein have been correlated with negative patient survival. Cdc42 has also been shown to be required for both G1-S phase progression and mitosis, and it also modulates the transcription factors SRF, STAT3, and NFkB:
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Ye teaches that the role of Cdc42 in cervical cancer, immunohistochemistry was used to detect Cdc42 expression in three types of tissues: normal cervical tissues, cervical intraepithelial neoplasia (CIN) I or below, CIN II or above, and cervical cancer tissues. Cdc42 expression was gradually increased showing significant difference and was significantly higher in HeLa cells than in regular cells. The migration ability of HeLa cells transfected with Cdc42 was higher than that of non-transfected cells. It was proposed that the overexpression of Cdc42 can promote filopodia formation in HeLa cells. Cdc42 overexpression significantly improved the ability of cervical cancer cells to migrate, possibly due to improved pseudopodia formation:
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Zins teaches that the small molecular inhibitor AZA197 has been used to inhibit Cdc42 in the treatment of KRAS mutant colorectal cancers. There was evidence that Cdc42 inhibition by AZA197 treatment suppresses proliferative and pro-survival signaling pathways via PAK1-ERK signaling and reduces colon cancer cell migration and invasion. In mice, systemic AZA197 treatment in vivo reduced primary tumor growth and prolonged survival. Therapy targeting Rho GTPase Cdc42 signaling pathways can be effective for treatment of patients with advanced colon cancer overexpressing Cdc42, and particularly those with KRAS-mutant disease.
Moreover, Stengel teaches that Cdc42 is overexpressed in non-small cell lung cancer, colorectal adenocarcinoma, melanoma, breast cancer, and testicular cancer. Elevated levels of the protein have been correlated with negative patient survival. Cdc42 has also been shown to be required for both G1-S phase progression and mitosis, and it also modulates the transcription factors SRF, STAT3, and NFkB.
See also Qadir (“Cdc42, an evolutionary member of Rho GTPase family, is responsible for switching on variety of cellular responses such as cell polarity, cytoskeleton remolding, proliferation, migration, cellular transformation, filopodia and invadopodia formation, invasion, enzyme activity, adhesion membrane trafficking, and transportation. Deregulation of Cdc42 may lead to the development of oncogenic condition. Therefore, it can be concluded that inhibiting the overexpression of Cdc42, cancer progression can be controlled. Hence, deeper knowledge about the mechanism of cancer progression involving Cdc42 can lead to a new era for the development of Cdc42 inhibitors in favor of cancer management at molecular level.”)
The difference between the applied references and the claimed inventions is that the references do not teach the invention with particularity so as to amount to anticipation (See M.P.E.P. § 2131: "[t]he identical invention must be shown in as complete detail as is contained in the ... claim." Richardson v. Suzuki Motor Co., 868 F.2d 1226, 1236, 9 USPQ2d 1913, 1920 (Fed. Cir. 1989). The elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990).). However, based on the above, the references teach the elements of the claimed invention with sufficient guidance, particularity, and with a reasonable expectation of success, that the invention would be prima facie obvious to one of ordinary skill (the prior art reference teaches or suggests all the claim limitations with a reasonable expectation of success. See M.P.E.P. § 2143).
Moreover, one or more dependent claims cover effective amounts. However, the amount of a Cdc42 inhibitor in any therapeutic composition would be a result-effective parameter that will affect the pharmacological and pharmacokinetic properties of the final composition. In this manner, the amount of a specific ingredient in a composition is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize.
Specifically, it would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve a desired result. For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually rats, rabbits, dogs, or pigs. The animal model also can be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
Therapeutic efficacy and toxicity, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population), can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED5o. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect. Factors which can be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered once or twice daily every 3 to 4 days, every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation.
Normal dosage amounts can vary from micrograms to 100,000 micrograms, up to a maximum total dose, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
In this way, optimization of these parameters is a routine practice, and consequently, would be prima facie obvious, absent factual evidence demonstrating an unexpected benefit of the claimed amount(s).
The applied references do not teach the recited compounds as Cdc42 inhibitors. However, Zheng II is combined for the proposition that the recited compounds are identified as Cdc42 inhibitors:
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see definitions at paragraphs 0143+.
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In this way, Zheng teaches that the particular known technique of using the recited compounds as Cdc42 inhibitors was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to those methods that use Cdc442 inhibitors, such as the methods of treating cancer, as disclosed in the primary references, would have yielded predictable results. Accordingly, using the recited compounds as Cdc42 inhibitors for the purposes of treating cancer would have been prima facie obvious.
Claims 20 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over: Zheng, et al., 2011, Cellular Signalling. 23 (9) (Zheng); or 1415–23; Ye et al., 2015, International Journal of Oncology (Ye); 46 (2): 757–63; or Zins et al., 2013, Journal of Translational Medicine, 11: 295 (Zins); or Stengel et al., Cellular Signalling, 2011, 23 (9): 1415–23, newly cited (Stengel), or Qadir et al., 2015, Biol Drug Des, 86: 432-439 (Qadir), newly cited; in view of:
U.S. Publication No. 20110020274 based on an application by Zheng (Zheng II); in further view of:
Yan et al., Front Immunol. 2018 Jul 27; 9:1739 (Yan).
The rejected claims cover combination therapies with immune checkpoint inhibitors. However, Yan discusses that these regimens are part of anti-cancer strategies:
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Therefore, those of ordinary skill would have reason to combine combining Cdc42 inhibitors with immune checkpoint inhibitors to see if there is a synergistic or added therapeutic benefit, and therefore, such combination therapies would have been prima facie obvious.
Applicant argues that the references do not provide a reasonable expectation that CDC42 inhibition could treat cancers.
However, the references provide a foundation that cdc42 is implicated in oncogenesis, progression and metathesis. For example, Zins explicitly teaches that targeting Cdc42 with the small molecule drug AZA197 suppresses primary colon cancer growth and prolongs survival in a preclinical mouse xenograft model by downregulation of PAK1 activity. Specifically, Zins teaches that the small molecular inhibitor AZA197 has been used to inhibit Cdc42 in the treatment of KRAS mutant colorectal cancers. There was evidence that Cdc42 inhibition by AZA197 treatment suppresses proliferative and pro-survival signaling pathways via PAK1-ERK signaling and reduces colon cancer cell migration and invasion. In mice, systemic AZA197 treatment in vivo reduced primary tumor growth and prolonged survival. Therapy targeting Rho GTPase Cdc42 signaling pathways may be effective for treatment of patients with advanced colon cancer overexpressing Cdc42, and particularly those with KRAS-mutant disease.
Moreover, Stengel teaches that Cdc42 is overexpressed in non-small cell lung cancer, colorectal adenocarcinoma, melanoma, breast cancer, and testicular cancer. Elevated levels of the protein have been correlated with negative patient survival. Cdc42 has also been shown to be required for both G1-S phase progression and mitosis, and it also modulates the transcription factors SRF, STAT3, and NFkB:
(“The acquisition of an invasive and motile phenotype is critical for tumor progression and mestastasis. Metastasis is a complex process in which cancer cells must migrate out of the primary tumor site, invade surrounding tissue, intravasate into the blood or lymphatic system, survive while in circulation, and extravasate and initiate metastatic outgrowth at distant organ sites. A number of studies have implicated Cdc42 function in the regulation of multiple steps of this process. Consistently, studies in human cancer models have identified Cdc42 as an important regulator of metastasis… The mechanisms by which Cdc42 activation contributes to oncogenesis, including what signaling pathways activated downstream of Cdc42 are essential for the induction of cellular transformation, have been under active investigation. In yeast, Cdc42 is known to be required for cell division. Similarly, Cdc42 has been shown to be involved in mammalian cell cycle progression. In fact, Cdc42 seems to be required for both G1-S phase progression and mitosis. In addition to promoting cell proliferation, Cdc42 has been implicated in regulating cancer cell survival, as well as modulating the transcription factors such as SRF, STAT3 and NFkB, which are further involved in the cell growth and survival. These proliferative and survival roles of Cdc42 in cancer biology have been extensively reviewed elsewhere”).
See Qadir (“Deregulation of Cdc42 may lead to the development of oncogenic condition. Therefore, it can be concluded that inhibiting the overexpression of Cdc42, cancer progression can be controlled.”).
Therefore, the references provide a reasonable expectation that CDC42 inhibition could treat cancers.”
Again, Zheng II is applicable since it identifies the recited compounds as agents that inhibit Cdc42. In particular, Zheng II teaches that the particular known technique of inhibiting Cdc42 with the instant compounds was recognized as part of the ordinary capabilities of one skilled in the art. The motivation to combine the references is provided by their respective teachings. Namely, those of ordinary skill would have applied the known technique to treating cancer since Cdc42 has been shown to actively assist in cancer progression, see primary references.
Conclusive proof that the recited compounds can treat cancer is not required, see MPEP 21434.02 (“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")).
Here, those of ordinary skill would have yielded a reasonable expectation of treating cancer with the recited compounds since the recited compounds have been shown to inhibit Cdc42, which has been implicated in oncogenesis and cancer proliferation. Therefore, the rejection is maintained.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARL J PUTTLITZ whose telephone number is (571)272-0645. The examiner can normally be reached on Monday to Friday from 9 a.m. to 5 p.m.
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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646