DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 12, 2025 has been entered.
2, Claims 1-43 and 47 were cancelled. Claims 44 and 48 have been amended. New claims 50-53 have been added.
3. Claims 44-46 and 48-53 are currently pending and under consideration
Priority
4. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications fail to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. Examiner has established a priority date of August 17, 2022 for claims 44-46 and 49-53 because the claims as currently constituted recite “a small molecule N-heteroaryl compound containing: (a) a nitrogen in the N-heteroaryl ring system, (b) an aryl or heteroaryl group, and (c) an acrylamide-based Michael acceptor that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR” and a review of the parent applications does not reveal the claimed limitations. See also the new matter rejection below. Applicant is invited to submit evidence pointing to the serial number, page and line where support can be found establishing an earlier priority date.
Additionally, claim 48 has a priority date of February 03, 2005 based on the disclosure of Applications 60/649,483.
Response to Arguments
5. Applicant argues that the requisite support and enablement under pre-AIA 35 U.S.C. § 112, first paragraph for amended claim 44 can at least be found in U.S. Provisional Application No. 60/649,483, filed February 3, 2005, at paragraphs [005], [007], [008], [0017], [0066], and [0067] and Figure 3. With respect to amended claims 45 and 46, Applicants reiterate that the requisite support and enablement under pre-AIA 35 U.S.C. § 112, first paragraph can at least be found in U.S. Provisional Application No. 60/649,483, filed February 3, 2005, at paragraphs [0033] and [0035]. In addition, support for new claim 49 can at least be found in U.S. Provisional Application No. 60/649,483, filed February 3, 2005, at paragraph [0034].
Applicant argues that the requisite support and enablement under pre-AIA 35 U.S.C. § 112, first paragraph for new claims 50-53 can at least be found in U.S. Provisional Application No. 60/671,989, filed April 15, 2005, on at least pages 25-35 of the detailed description, in the Methods and Examples sections, and in the Figures, such as Figures 6, 8A, and 9.
Applicant argues that accordingly, Applicants submit that amended claims 44-46 of the instant application are at least provided the requisite support and enablement under pre-AIA 35 U.S.C. § 112, first paragraph, by U.S. Provisional Application No. 60/649,483, filed February 3, 2005, and therefore entitled to at least a priority date of February 3, 2005. In addition, Applicants submit that new claims 50-53 are at least provided the requisite support and enablement under pre-AIA 35 U.S.C. § 112, first paragraph by U.S. Provisional Application No. 60/671,989, filed April 15, 2005, and therefore entitled to at least a priority date of April 15, 2005.
Applicant’s arguments have been considered, but have not been found persuasive. With regard to claim 44 and paragraphs [005], [007], [008], [0017], [0066], and [0067] and Figure 3, the ‘483 application teaches the general structure of EGFR, the reversible EGFR inhibitors Gefitinib and Erlotinib, and the irreversible inhibitors HKI 357 and EKB 359. However, the cited support does not provide an adequate description of the broadly claimed small molecule N-heteroaryl compound that binds to cysteine 773 residue in the ligand binding pocket of EGFR in the ligand binding pocket of EGFR because HKI-357 and EKB-569 are only two species of the broadly claimed cysteine 773 binder and Gefitinib and Erlotinib do not contain an acrylamide-based Michael acceptor. HKI-357 and EKB-569 are both 3-cyanoquionlines with a single ethyl ether moiety at the 7 position of the quinolone and a (dimethyl amino)but-2-enamide at the 6 position of the quinolone. HKI-357 has a 3-chloro-4(3-fluorophenyl) methoxy]anilino group and EKB-569 has a 3-chloro-(4-fluorophenyl) anilino group. However, the claimed small molecule N-heteroaryl compound that binds to cysteine 773 is not limited to an inhibitor comprising a 3-cyanoquionline with a single ethyl ether moiety at the 7 position of the quinolone, a 3-cyanoquionline with specific anilino compounds or 2-enamides bound to the 3-cyanoquionline. Thus, the disclosure of Gefitinib, Erlotinib HKI-357 and EKB-569 in the ‘483 application does not provide adequate support for the broadly claimed genus of a small molecule N-heteroaryl compound that binds to cysteine 773 residue in the ligand binding pocket of EGFR or administering effective amounts thereof as effective amounts are not taught for any of the species within the genus.
With regard to claims 45 and 46 and paragraphs [0033] and [0035] in the ‘483 application, although paragraphs [0033] and [0035] disclose the outcomes of delivering an effective amount of an irreversible inhibitor, they do not teach administering the claimed small molecule N-heteroaryl compound to achieve said outcomes. Thus, given that claims 45 and 46 depend on claim 44 and incorporate by reference the limitations of claim 44, the ‘483 application does not describe the method as claimed.
With regard to claim 49 and paragraph [0034] in the ‘483 application, although paragraph [0034] discloses using other tyrosine kinase inhibitors, it does not teach administering the claimed small molecule N-heteroaryl compound to achieve said outcomes. Thus, given that claim 49 depends on claim 44 and incorporate by reference the limitations of claim 44, the ‘483 application does not describe the method as claimed.
With regard claims 50-53, although the ‘989 application teaches the additional EGFR inhibitor HKI-272, metastatic non-small cell lung cancer, the deletion delE746-A750, the L858R and T790M mutation, it does not teach administering the claimed small molecule N-heteroaryl compound to treat a metastatic NSCLC. Thus, given that claims 50-53 depend on claim 44 and incorporate by reference the limitations of claim 44, the ‘989 application does not describe the method as claimed.
Rejections Maintained/Modified
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
6. Claims 44-46 and 49-53 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement essentially for the reasons of record set forth below. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Amended claims 44-46 and 49-53 are drawn “a small molecule N-heteroaryl compound containing: (a) a nitrogen in the N-heteroaryl ring system, (b) an aryl or heteroaryl group, and (c) an acrylamide-based Michael acceptor that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR”.
Applicant argues that support for the amended claims and the new claim can be found at least in paragraph [0027] and Figures 2B and 6, of the original application as filed.
Regarding the broadly claimed small molecule N-heteroaryl compound that covalently binds to cysteine 773 a review of the cited support reveals support for Gefitinib, Erlotinib, EKB-569 (4-anilinoquinoline-3-carbonitrile), HKI-357 (a derivative of 4-anilinoquinoline-3-carbonitrile) HKI-272 (a derivative of 4-anilinoquinoline-3-carbonitrile), CL-387,785 and binding to cysteine 773 of in paragraph [0027] and Figures 2B and 6. However, the disclosure of Gefitinib, Erlotinib, HKB-569, HKI-272, and HKI-357 which all have chloride moieties at position 3 of the aniline group and bind to cysteine 773 of EGFR fails to provide adequate support for the broader claimed genus of “a small molecule N-heteroaryl compound containing: (a) a nitrogen in the N-heteroaryl ring system, (b) an aryl or heteroaryl group, and (c) an acrylamide-based Michael acceptor that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR” because Gefitinib and Erlotinib do not contain an acrylamide-based Michael acceptor and the genus includes a myriad compounds that are distinct in structure from the disclosed HKB-569, HKI-272, and HKI-357 compounds and the three species are insufficient to describe the newly claimed genus of “a small molecule N-heteroaryl compound containing: (a) a nitrogen in the N-heteroaryl ring system, (b) an aryl or heteroaryl group, and (c) an acrylamide-based Michael acceptor that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR”. Additionally, HKB-569, HKI-272, and HKI-357 all have only a single species of ether and a single species of dimethyl amino aryl or heteroaryl substituted on a quinoline moiety. These few species fail to describe the claimed genus. Thus, “a small molecule N-heteroaryl compound containing: (a) a nitrogen in the N-heteroaryl ring system, (b) an aryl or heteroaryl group, and (c) an acrylamide-based Michael acceptor that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR” is new matter.
Response to Arguments
7. Applicant argues that independent claim 44 is amended to be directed to: “[a] method for killing gefitinib and/or erlotinib resistant non-small cell lung cancer cells in a patient, comprising administering to the patient a therapeutically effective amount of a small molecule N-heteroaryl compound containing: (a) a nitrogen in the N-heteroaryl ring system, (b) an aryl or heteroaryl group, and (c) an acrylamide-based Michael acceptor, that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR,” without prejudice or disclaimer.
Applicant argues that the amended claims cover only those EGFR inhibitors that are capable of accessing the intracellular tyrosine kinase domain of EGFR (ATP binding site) and covalently binding to the designated cysteine residue in the ligand-binding pocket of the kinase domain, thereby providing irreversible inhibition.
Applicant argues that in the Office Action, the Office stated that “Fry 1998 (IDS) teaches that the position of the enamide on the same scaffold can significantly affect the activity of the inhibitor” and that “Fry 1998 teaches this difference is a result of the 6-acrylamide being in closer proximity to Cys-773 of EGFR than the 7-acrylamide on the quinazoline. .. .. So even small positional changes of the enamide on the same core structure can significantly affect activity of the inhibitor.” Office Action at page 22. Applicants respectfully disagree and traverse.
The Molecular Modeling section of Fry 1998 examines binding modes of certain quinazolines and explains differences in binding activities due to certain features. Specifically, Fry 1998 teaches that 6-acrylamide analogs alkylate Cys-773 “much more rapidly than the [sic] those possessing a 7-acrylamide.” Fry 1998 at 12025 (emphasis added). Accordingly, Fry 1998 does not teach that small positional changes lack capacity to covalent bind Cys-773, rather that these positional changes affect the kinetic of binding (rapid vs. not rapid). However, the amended claims do not require specific kinetic limitations in covalently binding Cys-773. The claims only require compounds with the structural features a) through c). These structural features were well known in the art prior to or at the time of filing the present application as explained in the Response to the Non-Final Office Action of June 20, 2024, filed October 21, 2024 (“Response”), which is incorporated herein in its entirety.
Applicant argues that as discussed in the Response in Section IV, b and c, irreversible EGFR inhibitors were known in the art prior to the priority application and the as-filed specification provides adequate written description by providing the structure and a representative number of species.
Applicant argues that thus, one of ordinary skill in the art would clearly understand that the disclosure based on the exemplary irreversible EGFR TKIs in the specification (i.e., EKB-569, HKI-272, and HKI-357) is equally applicable to additional small molecule N-heteroaryl irreversible EGFR TKIs. As previously explained, a person of ordinary skill in the art at the relevant time was familiar with a small molecule TKI based on an N-heteroaryl scaffold containing an aryl or heteroaryl group in the lipophilic region and a Michael acceptor, particularly acrylamide-based, which can access the designated cysteine of the kinase domain for covalent bond formation, thereby affording irreversible inhibition.
Applicant argues that many irreversible EGFR inhibitors were known at the time of filing and a person of ordinary skill in the art had knowledge of the common structural features of irreversible EGFR inhibitors as required by the amended claims. Since the claims are directed to method of treatment, not compounds, a person of ordinary skill in the art would have been able to perform the claimed methods for the reasons as discussed herein.
Applicant argues that accordingly, at least for the reasons as discussed herein and in the Response one skilled in the relevant art would have found that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicants respectfully request that the rejection under 35 U.S.C. § 112(a), or 35 U.S.C. § 112 (pre-AIA ), first paragraph, be withdrawn.
Applicant's arguments been considered, but have not been found persuasive. Although irreversible EGFR inhibitors were known in the art and EKB-569, HKI-272 or HKI-357 were specifically disclosed in the specification, the claimed “a small molecule N-heteroaryl compound containing: (a) a nitrogen in the N-heteroaryl ring system, (b) an aryl or heteroaryl group, and (c) an acrylamide-based Michael acceptor that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR” is not limited to the structures of known or disclosed irreversible EGFR inhibitors. The claimed small molecule N-heteroaryl compound is not limited to containing a N-heteroaryl ring system of the known or disclosed irreversible EGFR inhibitors (quinazoline, quinoline) with the acrylamide based Michael acceptor at positions in the ring structure that are known to be effective for covalent binding of cysteine 773. Additionally, HKB-569, HKI-272, and HKI-357 all have only a single species of aryl or heteroaryl group on a quinoline moiety, while the claimed compounds encompass any aryl or heteroaryl group substituents.
As previously set forth, the structure scaffold and R groups of the known irreversible EGFR inhibitors make specific contacts with the EGFR or HER-2 kinase to mediate their binding to cysteine 773 in EGFR or cysteine 805 HER-2 kinase. Tsou 2005 (IDS) teaches that in the model of the HER-2 and HKI-272/250 complex,
. . . the N1 atom of the quinoline is hydrogen bonded to the backbone NH of Met 801 at a distance of 3.32 Å. The cyano nitrogen is 2.76 Å from the OH of Ser 783. The chloroaniline portion of the inhibitor is surrounded by residues Thr 798, Lys 753, Leu 133, Thr 143, and Asp 144, while the pyridylmethoxy group lies in a pocket surrounded by Val 773, Met 774, Arg 784, Ser 783, Val 777, Phe 864, and Thr 862.
See p. 1111-right column and Figs. 1 and 2.
These specific structures and contacts for binding cysteine 773 residue would not necessarily be achieved by the broadly claimed small molecule N-heteroaryl compound which is not limited to any of the known or disclosed structures for EGFR inhibitors.
Regarding Fry 1998 (IDS) although the claims do not require specific kinetic limitations in covalently binding Cys-773, the teachings of Fry demonstrate that even small structural changes in a protein binding small molecule can change its activity and/or function. As previously set forth, Fry 1998 teaches that placement of the acrylamide side chain at the 6 position (PD 168393) of the quinazoline allows a much more rapid irreversible interaction than placement of the acrylamide at the 7- position (PD 160678). See Figs. 1 and 2 and p. 12024-right column. Fry 1998 teaches this difference is a result of the 6-acrylamide being in closer proximity to Cys-773 of EGFR than the 7-acrylamide on the quinazoline. See p. 12025-Molecular Modeling and Fig. 5. So even small positional changes of the enamide on the same core structure can significantly affect activity of the inhibitor. Thus, given the importance of the specific structure for activity of small molecules like the irreversible EGFR inhibitors and the breadth of the claimed structures, the broadly claimed genus of “a small molecule N-heteroaryl compound containing: (a) a nitrogen in the N-heteroaryl ring system, (b) an aryl or heteroaryl group, and (c) an acrylamide-based Michael acceptor that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR” was not fully known or described in the art at the time the invention filed and one of skill in would not have been in possession the broadly claimed small molecule N-heteroaryl that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR.
Although Applicant argues that a person of ordinary skill in the art had knowledge of the common structural features of irreversible EGFR inhibitors as required by the amended claims, MPEP 2163 (II)(A)(3)(a) teaches: “An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004)”. Thus, the ability to design “a small molecule N-heteroaryl compound containing: (a) a nitrogen in the N-heteroaryl ring system, (b) an aryl or heteroaryl group, and (c) an acrylamide-based Michael acceptor that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR” does not provide an adequate description of the broadly claimed irreversible small molecule N-heteroaryl compound that covalently binds to cysteine 773, which includes structures not known in the art or disclosed in the specification at the time the application was filed.
Although the specification as filed generally refers to irreversible EGFR inhibitors and discloses a few species of irreversible EGFR inhibitors, this does not provide support for the subgenus of “a small molecule N-heteroaryl compound containing: (a) a nitrogen in the N-heteroaryl ring system, (b) an aryl or heteroaryl group, and (c) an acrylamide-based Michael acceptor that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR” currently claimed for the reasons set forth above and the introduction of claim changes which involve narrowing the claims by introducing elements or limitations which are not supported by the as-filed disclosure is a violation of the written description requirement of 35 U.S.C. 112, first paragraph. See MPEP 2163.05 (II). See also In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (“Whatever may be the viability of an inductive-deductive approach to arriving at a claimed subgenus, it cannot be said that such a subgenus is necessarily described by a genus encompassing it and a species upon which it reads.”)
Thus, for the reasons previously set forth and above, the claimed small molecule N-heteroaryl compound containing: (a) a nitrogen in the N-heteroaryl ring system, (b) an aryl or heteroaryl group, and (c) an acrylamide-based Michael acceptor that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR is not adequately described in the specification and claims as filed and is new matter. Therefore the rejection is maintained.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
8. Claim(s) 44-46 and 49-53 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by US 2010/0087482 A1 (Haber et al. Apr. 8, 2010), “Haber”.
Haber teaches in claims 1-3:
1. A method for treating gefitinib and/or erlotinib resistant cancer, comprising the steps of: a. monitoring progression of a cancer in a subject at a time point after the subject has initiated gefitinib and/or erlotinib treatment, wherein progression of the cancer is indicative of cancer that is resistant to gefitinib and/or erlotinib treatment; and b. administering to the subject having a cancer that is resistant to gefitinib and/or erlotinib treatment a pharmaceutical composition comprising an irreversible epidermal growth factor receptor (EGFR) inhibitor.
2. The method of claim 1, wherein the irreversible EGFR inhibitor is selected from the group consisting of EKB-569, HKI-272 and HKI-357.
3. The method of claim 1, wherein the irreversible EGFR inhibitor binds to cysteine 773 of EGFR (SEQ ID NO: 1).
Haber teaches EKB-569 ((E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide), HKI-357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide), HKI-272 ((E)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide), CL-387,785 and binding to cysteine 773 of EGFR. See Fig. 2B and ¶¶ [0014], [0032], [0073], [0081] and [0088].
Haber teaches that the cancer is non-small lung cancer. See ¶ [0018] and claims 10 and 20.
Haber teaches administering an effective amount of the irreversible EGFR inhibitors. See ¶ [0032].
Haber teaches an "effective amount" indicates an amount that results in a beneficial effect for at least a statistically significant fraction of patients, such as an improvement of symptoms, a cure, a reduction in disease load, reduction in tumor mass or cell numbers, extension of life, or improvement in quality of life. See ¶ [0038].
Haber teaches an effective dose of 2 to 500 mg. See ¶ [0039].
Haber teaches that the irreversible inhibitors demonstrate increased killing of NSCLC cells harboring an EGFR mutation, compared with cells expressing wild-type receptor. See ¶¶ [0081] and [0085] and Figs. 2A 4B.
Haber teaches oral administration. See ¶¶ [0041], [0045] and [0052].
Haber teaches the treatment may also involve a combination of treatments, including, but not limited to a tyrosine kinase inhibitor in combination with other tyrosine kinase inhibitors. See ¶ [0033].
Haber teaches treating gefitinib resistant metastatic non-small cell lung cancer cells with a T790M EGFR mutation and a L858R EGFR sensitizing mutation and/or a de1E746-A750 deletion mutation to suppress proliferation of the cells with irreversible EGFR inhibitors, like HKI-357 and HKI-272. See ¶¶ [0023], [0025], [0037] [0079-0081], and [0085] and Figs. 1, 2 and 4.
Haber teaches gefitinib/erlotinib sensitivity may be predicted by the presence in the tumor of EGFR mutations including, for example, deletion of residues 747 (lysine) to 749 (glutamic acid) combined with a mutation in 750 (alanine), deletion of residues 747 (lysine) to 750 (alanine), substitution of arginine for leucine at residue 858. See ¶¶ [0034].
Response to Arguments
9. Applicant argues that claims 44-46, as amended, are entitled to the priority date of U.S. Provisional Application No. 60/649,483, filed February 3, 2005, at least for the reasons as discussed herein, thus, obviating the novelty rejection.
Applicant argues that Claim 48 is entitled to the priority date of U.S. Provisional Application No. 60/649,483, filed February 3, 200, as acknowledged by the Office. Office Action at page 9. Thus, the novelty rejection should be rendered moot.
Applicant argues that Claim 49 as amended, is entitled to the priority date of U.S. Provisional Application No. 60/649,483, filed February 3, 2005, at least for the reasons as discussed herein, thus, obviating the novelty rejection.
Accordingly, Applicants respectfully request the rejection against claims 28-29, 35, 38- 41, 43-46, 48 and 49 for lack of novelty be withdrawn.
Applicant’s arguments have been considered and have been found partially persuasive. The rejection of claim 48 is withdrawn given its priority support in the ‘483 application. However claims 44-46 and 49-53 have a priority date of August 17, 2022 for the reasons previously set forth and above. Thus, the rejections of claims 44-46 and 49-53 is maintained for the reasons previously set forth and above.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
10. Claims 44-46 and 49-53 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kwak et al. (Proc. Natl. Acad. Sci. May 24, 2005, 102: 7665-7670), “Kwak”, in view of US 2005/0059678 (Wissner et al. Mar. 17, 2005), “Wissner”.
Kwak teaches that irreversible inhibitors HKI-272, HKI-357 and EKB-569 inhibit the activity of a T790M, L858R and/or delE746-A750 mutated EGFR in metastatic non-small cell lung cancer cell (NSCLC) lines and suppress cell proliferation. See p. 7667-left col., p. 7668-right col., p. 7669 and Figs. 2-4.
Kwak teaches the irreversible inhibitors showed effective killing of NSCLC cells. See abstract, p.7668-left column, p.7669left column and Figs. 2A and 4B
Kwak teaches that these inhibitors bind EGFR via cys773 or cys805 of ERBB2. See p. 7668-left col.
Kwak teaches that HKI-272 may prove highly effective in the treatment of EGFR-mutant NSCLC that have become resistant to gefitinib or erlotinib. See abstract.
Kwak does not teach treating a NSCLC patient with an effective amount for treatment.
Wissner teaches treating cancer, including lung cancer, with 3-cyano quinolones like HKI-272 ((E)-N-[4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide). See ¶¶ 0007-0029 and claims 10-15.
Wissner teaches that the compounds may be administered in combination. See ¶ 0030.
Wissner teaches at paragraph 0031:
The compounds may be provided orally, by intralesional, intraperitoneal, intramuscular or intravenous injection; infusion; liposome-mediated delivery; topical, nasal, anal, vaginal, sublingual, uretheral, transdermal, intrathecal, ocular or otic delivery. In order to obtain consistency in providing the compound of this invention it is preferred that a compound of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 300 mg of a compound of the invention and preferably from 2 to 100 mg. Still further preferred unit dosage forms contain 5 to 50 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compounds may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day. The effective amount will be known to one of skill in the art; it will also be dependent upon the form of the compound. One of skill in the art could routinely perform empirical activity tests to determine the bioactivity of the compound in bioassays and thus determine what dosage to administer.
It would have been prima facie obvious at the time the invention was made given that the level of skill in the art was high, e.g. a physician, to use the irreversible inhibitors HKI-272, HKI-357 and/or EKB-569 taught by Kwak and Wissner to treat a gefitinib and/or erlotinib resistant NSCLC having a T790M, L858R and/or delE746-A750 mutation in EGFR with a daily unit dose of 2-500 mg orally because Kwak teaches that irreversible inhibitors HKI-272, HKI-357 and EKB-569 inhibit the activity of a T790M mutant EGFR in non-small cell lung cancer cell (NSCLC) lines and suppress cell proliferation and that inhibitors like HKI-272, HKI-357 and EKB-569 may prove highly effective in the treatment of EGFR-mutant NSCLC that have become resistant to gefitinib or erlotinib and Wissner teaches treating cancer, including lung cancer, with 3-cyano quinolones like HKI-272 and teaches doses in the claimed range for daily, oral treatment. One of skill in the art could have readily optimized the dose administered to achieve the most effective therapy and because Wissner teaches one of skill in the art could routinely perform empirical activity tests to determine the bioactivity of the compound in bioassays and thus determine what dosage to administer.
Response to Arguments
11. Applicant argues that claims 44-46 as amended, are entitled to the priority date of U.S. Provisional Application No. 60/649,483, filed February 3, 2005, at least for the reasons as discussed herein, thus, obviating the obviousness rejection.
Applicant argues that Claim 48 is entitled to the priority date of U.S. Provisional Application No. 60/649,483, filed February 3, 200, as acknowledged by the Office. Office Action at pages 9 and 10. Thus, the obviousness rejection against claim 48 should be rendered moot.
Applicant argues that Claim 49 as amended, is entitled to the priority date of U.S. Provisional Application No. 60/649,483, filed February 3, 2005, at least for the reasons as discussed herein, thus, obviating the obviousness rejection.
Applicant argues that accordingly, Applicants respectfully request the rejection against claims 28, 29, 31, 32, 35, 38, 41, 43-46, 48 and 49 for lack of obviousness be withdrawn.
Applicant’s arguments have been considered and have been found partially persuasive. The rejection of claim 48 is withdrawn given its priority support in the ‘483 application. However claims 44-46 and 49-53 have a priority date of August 17, 2022 for the reasons previously set forth and above. Thus, the rejections of claims 44-46 and 49-53 is maintained for the reasons previously set forth and above.
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.
12. Claims 44-46 and 48-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 10,596,162 (Haber et al. Mar. 24, 2020) in view of US 2010/0087482 A1 (Haber et al. Apr. 8, 2010), “Haber”.
The ‘162 claims are drawn to:
1. A method of treating gefitinib and/or erlotinib resistant non-small cell lung cancer having a T790M mutation in SEQ ID NO: 1 in a patient, comprising administering daily to the patient having gefitinib and/or erlotinib resistant non-small cell lung cancer having a T790M mutation in SEQ ID NO: 1 a pharmaceutical composition comprising a unit dosage of 2-500 mg of an irreversible EGFR inhibitor that covalently binds to cysteine 773 of the catalytic domain within the SEQ ID NO: 1 having a T790M mutation; wherein the irreversible EGFR inhibitor is not CL-387,785.
2. The method of claim 1, wherein the irreversible EGFR inhibitor is selected from the group consisting of EKB-569, HKI-272 and HKI-357.
3. The method of claim 1, wherein the irreversible EGFR inhibitor is HKI-272.
4. The method of claim 1, wherein the irreversible EGFR inhibitor covalently binds to cysteine 805 in the ligand-binding pocket of ERBB2
The ‘162 claims teach as set forth above, but do not teach, treating metastatic NSCLC, treating NSCLC with a mutation of claims 51-53, or explicitly killing the cells in the patient.
Haber teaches as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘162 claims and Haber and orally treat a metastatic NSCLC with a T790M mutation, a L858R mutation, and/or a de1E746-A750 mutation with the irreversible EGFR inhibitors of the ‘162 claims and Haber to kill the NSCLC cells because Haber teaches oral treatment, treating gefitinib resistant metastatic non-small cell lung cancer cells with a T790M mutation, a L858R mutation, and/or a de1E746-A750 mutation with irreversible EGFR inhibitors to suppress proliferation and kill the NSCLC cells. Thus, one would have been motivated to treat a metastatic NSCLC with a T790M mutation, a L858R mutation, and/or a de1E746-A750 mutation because Haber teaches irreversible EGFR inhibitors suppress proliferation and kill the NSCLC cells.
13. Claims 44-46 and 48-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,603,314 (Haber et al. Mar. 31, 2020), in view of US 2010/0087482 A1 (Haber et al. Apr. 8, 2010), “Haber”.
The ‘314 claims teach:
1. A method for treating gefitinib and/or erlotinib resistant non-small cell lung cancer in a patient in need thereof, comprising administering daily to the patient having gefitinib and/or erlotinib resistant non-small cell lung cancer a pharmaceutical composition comprising a unit dosage of an irreversible epidermal growth factor receptor (EGFR) inhibitor that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR or cysteine 805 residue in the ligand-binding pocket of erb-B2.
2. The method of claim 1, wherein the irreversible EGFR inhibitor is EKB-569 or HKI-357.
3. The method of claim 1, wherein the irreversible EGFR inhibitor covalently binds to cysteine 773 residue of EGFR.
4. The method of claim 1, wherein the irreversible EGFR inhibitor covalently binds to cysteine 805 residue of erb-B2.
5. The method of claim 1, wherein the method further comprises administering at least one other tyrosine kinase inhibitor.
6. The method of claim 1, wherein the method further comprises administering radiation.
7. The method of claim 1, wherein the route of administering is intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, intrapleural, intrauterine, rectal, vaginal, topical, or intratumor.
8. The method of claim 1, wherein the route of administering is transmucosal or transdermal.
9. The method of claim 1, wherein the route of administering is oral.
The ‘314 claims teach as set forth above, but do not teach a daily dose of 2-500 mg, treating metastatic NSCLC, treating NSCLC with a mutation of claims 39 or 40 or killing the NSCLC cells.
Haber teaches as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘314 claims and Haber and orally treat a metastatic NSCLC with a T790M mutation, a L858R mutation, and/or a de1E746-A750 mutation with the irreversible EGFR inhibitors of the ‘314 claims and Haber at a daily dose of 2-500 mg to kill the NSCLC cells because Haber teaches treating with a daily dose of 2-500 mg and treating gefitinib resistant metastatic non-small cell lung cancer cells with a T790M EGFR mutation and a L858R EGFR sensitizing mutation with irreversible EGFR inhibitors to suppress proliferation and kill the NSCLC cells. Thus, one would have been motivated to treat a metastatic NSCLC with a T790M mutation, a L858R mutation, and/or a de1E746-A750 mutation because Haber teaches irreversible EGFR inhibitors suppress proliferation and kill the NSCLC cells.
14. Claims 44-46 and 48-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 7-12 of U.S. Patent No. 8,715,665 (Janne et al. May 6, 2014) in view of US 2010/0087482 A1 (Haber et al. Apr. 8, 2010), “Haber”.
The ‘665 claims teach:
1. A method for treating non-small cell lung cancer (NSCLC) or gastric cancer in a patient with an acquired resistance to treatment with an anti-ErbB therapeutic, comprising the steps of: a) selecting a patient with NSCLC or gastric cancer associated with an ErbB activating mutation or an ErbB gene amplification who has developed a resistance to treatment with an anti-ErbB therapeutic, and whose cancer cells comprise cells with a MET activating mutation or a MET gene amplification that reduces downregulation of PI3K/Akt signaling in response to the anti-ErbB therapeutic, and b) administering to said patient an anti-ErbB therapeutic and an anti-MET therapeutic.
2. The method of claim 1, wherein the subject has an EGFR, ErbB2, ErbB3, or ErbB4 activating mutation or gene amplification.
3. The method of claim 2, wherein the subject has an EGFR activating mutation or an EGFR gene amplification.
4. The method of claim 1, wherein the cancer is resistant to treatment with one or more of the following anti-ErbB therapeutics: an anti-EGFR therapeutic, an anti-ErbB2 therapeutic, an anti-ErbB3 therapeutic, or an anti-ErbB4 therapeutic.
5. The method of claim 1, wherein the cancer is resistant to treatment with one or more of the following anti-ErbB therapeutics: a small molecule therapeutic, a nucleic acid therapeutic, or a protein therapeutic.
7. The method of claim 5, wherein the cancer is resistant to treatment with an ErbB kinase inhibitor.
8. The method of claim 5, wherein the cancer is resistant to treatment with an EGFR kinase inhibitor.
9. The method of claim 1, wherein the anti-ErbB therapeutic is selected from the group consisting of gefitinib, erlotinib, lapatinib, PF00299804, CI-1033, EKB-569, BIBW2992, ZD6474, AV-412, EXEL-7647, HKI-272, cetuximab, pantinumumab, and trastuzumab.
10. The method of claim 1, wherein the anti-MET therapeutic is selected from the group consisting of PHA-665,752, SU11274, SU5416, PF-02341066, XL-880, MGCD265, XL184, ARQ 197, P-470, SGX-523, JNJ38877605, AMG 102, and OA-5D5.
11. The method of claim 1, wherein: a) the anti-ErbB therapeutic is selected from the group consisting of gefitinib, erlotinib, lapatinib, PF00299804, CI-1033, EKB-569, BIBW2992, ZD6474, AV-412, EXEL-7647, HKI-272, cetuximab, pantinumumab, and trastuzumab; and b) the anti-MET therapeutic is selected from the group consisting of PHA-665,752, SU11274, SU5416, PF-02341066, XL-880, MGCD265, XL184, ARQ 197, P-470, SGX-523, JNJ38877605, AMG 102, and OA-5D5.
12. The method of claim 1, wherein the anti-ErbB therapeutic is gefitinib and the anti-MET therapeutic is PHA-665,752.
The ‘665 claims teach as set forth above, but do not teach treating metastatic NSCLC, treating NSCLC with a mutation of claims 51-53, or killing the NSCLC cells.
Haber teaches as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘665 claims and Haber and orally treat a metastatic NSCLC with a T790M mutation, a L858R mutation, and/or a de1E746-A750 mutation with a daily dose of 2-500 mg of the irreversible EGFR inhibitors of the ‘665 claims and Haber to kill the NSCLC cells because Haber teaches oral treatment, a daily dose of 2-500 mg, and treating gefitinib resistant metastatic non-small cell lung cancer cells with a T790M EGFR mutation and a L858R EGFR sensitizing mutation with irreversible EGFR inhibitors to suppress proliferation and kill the NSCLC cells. Thus, one would have been motivated to treat a metastatic NSCLC with a T790M mutation, a L858R mutation, and/or a de1E746-A750 mutation because Haber teaches irreversible EGFR inhibitors suppress proliferation and kill the NSCLC cells.
15. Claims 44-46 and 48-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 9,511,063 (Zacharchuk et al. Dec. 6, 2016) in view of US 2010/0087482 A1 (Haber et al. Apr. 8, 2010), “Haber”.
The ‘063 claims teach:
1. A method for treating a neoplasm in a patient in need thereof, consisting of administering to the patient: i) an effective amount of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or an ester, ether, carbamate, or a pharmaceutically acceptable salt thereof; and ii) vinorelbine, or a pharmaceutically acceptable salt thereof; wherein the neoplasm is selected from the group consisting of a lung cancer and breast cancer.
2. The method of claim 1, wherein the method administers an effective amount of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or a pharmaceutically acceptable salt thereof.
3. The method of claim 2, wherein the (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy) anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or pharmaceutically acceptable salt thereof, is administered in a unit dose.
4. The method of claim 3, wherein said unit dose is a tablet.
5. The method of claim 2, wherein one or both of the (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or pharmaceutically acceptable salt thereof, and the vinorelbine are delivered intravenously or orally to said patient.
6. The method of claim 2, wherein the (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy) anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or pharmaceutically acceptable salt thereof, is administered in an amount of at least about 120 mg.
7. The method of claim 6, wherein the (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy) anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or pharmaceutically acceptable salt thereof, is administered in an amount of at least about 160 mg.
8. The method of claim 7, wherein the (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy) anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or pharmaceutically acceptable salt thereof, is administered in an amount of at least about 240 mg.
9. The method of claim 2, wherein the (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy) anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or pharmaceutically acceptable salt thereof, is administered daily.
10. The method of claim 2, wherein the (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy) anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or pharmaceutically acceptable salt thereof, is administered at least once daily.
11. The method of claim 2, wherein the (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy) anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, or pharmaceutically acceptable salt thereof, is administered on day 1 of said regimen.
12. The method of claim 2, wherein the (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy) anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(di