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 .
Current Status
This action is responsive to the claims of 10/02/2025. Claims 1-17 are pending. Claims 4, 8, and 11 are withdrawn. Claims 1-3, 5-7, 9-10, and 12-17 have been examined on the merits.
Election/Restrictions
The remarks/amendments of 10/02/2025 did not overcome the pending prior art rejections and the rejections are maintained. Thus, the Markush search will not be unnecessarily extended in this action.
The elected species IRX4204, trastuzumab, and thyroxine read on claims 1-3, 5-7, 9-10, and 12-17.
Claims 4, 8, and 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of Her2-targeted therapeutic, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/06/2025.
Priority
The effective filing date remains 06/11/2019.
Response to Arguments
Examiner acknowledges receipt of and has reviewed the remarks and amendments of 10/02/2025, no new matter is found.
The objection to the specification is maintained since the amendments did not improve the resolution of the chemical formulas.
The objection to claims 1 and 5 (¶12 in prev. action) over resolution of Formula (I) is maintained since the amendment did not improve resolution.
The objection to claims 1 and 5 (¶13 in prev. action) over punctuation is withdrawn since applicant fixed the objected to punctuation.
The 112(f) interpretations of the claims 2-3, 6-7, 9-10, 14, and 17, as explained in ¶16 of the prev. action, still applies to the amended claims of 10/02/2025.
The 112(b) rejection of claim 5-7 and 13 (¶19 in prev. action) is withdrawn since Applicant has amended claim 5 to replace “the Her2 kinase inhibitor” with “the Her2-targeted therapeutic agent”.
The 112(b) rejection of claim 15-17 (¶20 in prev. action) is withdrawn since Applicant has amended the claim in line with Examiner’s suggestion.
The 103 rejection of claims 1-3, 5-7, 9-10, and 12-14 over IO, LIBY (evidenced by NCI), and MITRI is maintained. Applicant's arguments filed 10/02/2025 have been fully considered but they are not persuasive. Applicant appears to argue that each reference on its own does not teach or suggest all limitations of the rejected claims and the artisan would not be motivated to combine the references due to specific teachings of LIBY and MITRI. Regarding the first half of the argument, Examiner stresses the combination of the references is relied upon to teach the instant claims, not each reference individually.
Regarding LIBY, Applicant argues since LIBY suggests combination of IRX4204 and a synthetic triterpenoid the artisan would not be motivated to combine IRX4204 with a HER2 targeted therapeutic. Examiner respectfully disagrees; the teachings of LIBY does not teach away from other combination therapies (e.g., by teaching a specific combination is harmful or ineffective). Further, LIBY is directed to a method of treating HER2+ breast cancer with IRX4204. In view of In re Kerkhoven, the combination of drugs taught for the same purpose (i.e., targeting HER2) is obvious. Thus, the combination of IRX4204 and another HER2 targeted therapeutic is obvious (as discussed on Pg. 14 of the prev. action). Applicant further argues the artisan would not be motivated to combine IO and LIBY since IO does not describe treating HER2+ breast cancer. Examiner disagrees because IO and LIBY are each drawn to methods of treating cancer by administering the same compound IRX4204 (see teaching on Pg. 10-11 of prev. action). IO is broader in scope (i.e., breast cancer) and LIBY is drawn to a species thereof (i.e., HER2+ breast cancer). Therefore, the artisan would see these references as drawn to related applications of the same compound and, thus, would have reason to combine them. Regarding NCI, Examiner relies upon NCI as an evidentiary reference to support LIBY not to teach the instant claims.
Regarding MITRI, Applicant argues MITRI does not teach the instant combination of IRX4204 with trastuzumab, which was acknowledged by Examiner previously (Pg. 12 prev. action). Examiner relies upon MITRI to teach trastuzumab is a known HER2 targeted therapeutic which is best administered concurrent with another chemotherapy (see teachings on pg. 12 of prev. action). As stated above, In re Kerkhoven, provides motivation to combine two HER2 targeted therapeutics known in the art: trastuzumab and IRX4204. Further, Applicant argues the artisan would not be motivated to combine MITRI and IO since IO does not teach HER2+ breast cancer. However, in view of the combination of IO and LIBY (both concerning applications of IRX4204), the relevance of MITRI becomes clear as teaching another relevant HER2 therapeutic.
Since Applicant did not provide any evidence of unexpected/surprising results (see MPEP 716.02(a)) and the arguments are not found to be persuasive, the rejection is maintained.
The 103 rejection of claims 1, 5, 9, and 15-17 over IO, LIBY (evidenced by NCI), MITRI, and ROMOND is maintained. Applicant's arguments filed 10/02/2025 have been fully considered but they are not persuasive. Applicant’s arguments over IO, LIBY, NCI, and MITRI are discussed above. Applicant argues ROMOND does not teach or suggest the combination of IRX4204 with trastuzumab/a HER2 therapeutic; however, Examiner does not rely upon ROMOND for such teachings. Examiner relies upon ROMOND to teach dosages of trastuzumab for treatment of HER2+ breast cancer which can be used as a starting point for routine optimization. Applicant’s arguments did not address the merits of the routine optimization reasoning used by Examiner. Applicant further argues the artisan would have no motivation to combine ROMOND and IO since IO does not teach HER2+ breast cancer. However, much like MITRI, ROMOND is combined with the prior art references in combination. Since IO and LIBY each teach IRX4204 for treatment of cancer, LIBY teaches HER2+ breast cancer, and MITRI teaches another relevant HER2 therapeutic trastuzumab, the relevance of ROMOND becomes clear as teaching dosages of trastuzumab for HER2+ breast cancer.
Since Applicant did not provide any evidence of unexpected/surprising results (see MPEP 716.02(a)) and the arguments are not found to be persuasive, the rejection is maintained.
The non-statutory double patenting (NSDP) rejections of ¶28-34 are maintained. Examiner acknowledges Applicant’s statement of disagreement with the rejections; however, Applicant did not provide any argumentation and asked for the rejections to held in abeyance. Further, regarding the obviousness-type rejections, the arguments over IO, LIBY (NCI), MITRI, and ROMOND are not found persuasive (see ¶14-15). Thus, all of the previously presented NSDPs are maintained.
Specification - Maintained
The disclosure is objected to because of the following informalities: the chemical structures of Formula (I) and (II) on Pg. 11-12, 26-29, and 31-35 are of low resolution. Please provide higher resolution images. Appropriate correction is required.
Claim Objections - Maintained
Claims 1-3, 5-7, 12-13, and 15-16 are objected to because of the following informalities. Claims 1 and 5 recite the chemical structure of Formula (I); however, the image resolution is poor. Please provide a higher resolution image to improve readability. Dependent claims 2-3, 6-7, 12-13, and 15-16 are similarly objected to since they do not rectify the above issue. Appropriate correction is required.
Claim Rejections - 35 USC § 103 - Maintained
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, 5-7, 9-10, and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over IO (WO 2017/075612, filed in IDS of 06/19/2022) in view of LIBY (Liby, K., et al., Cancer Susceptibility and Prevention, 2007, 13(20), 6237-6243, filed in IDS of 06/19/2022), as evidenced by NCI (National Cancer Institute, NCI Dictionary of Cancer Terms, “Her2/neu,” archived on Wayback Machine 04/23/2008, retrieved from https://web.archive.org/web/20180423100811/https://www.cancer.gov/publications/dictionaries/cancer-terms/def/her2-neu on 06/23/2025), and MITRI (Mitri, Z., et al., Chemotherapy Research and Practice, 2012, 2012,1-7). These references were previously provided by Examiner (07/02/2025).
Determining the Scope and Contents of the Prior Art:
IO teaches specific RXR activation by an RXR agonist gives optimal anti-cancer activity when combined with administration of a thyroid hormone (Pg. 2 P5). IO teaches a method of treating breast cancer comprising administering an RXR agonist and a thyroid hormone (Pg. 35 claim 23) wherein the RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid (Pg. 33 claim 3), i.e., IRX4204
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, and the thyroid hormone is thyroxine (Pg. 33 claim 7). IO further teaches the method comprising administration of another anti-cancer agent (Pg. 36 claim 29). IO teaches IRX4204 activated RXR receptors with very high potency with EC50 < 0.5 nM (Pg. 23 Table 1) and selectively activates Nurr1/RXR heterodimer (Pg. 23 P88). IO also teaches IRX4204 inhibited growth of both ER-positive and -negative breast cancer cell lines in vitro with 74% efficacy in the ER-negative cell line (Pg. 26 Table 3).
LIBY teaches NRX194204
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(Pg. 6238 Fig. 1), which is the same compound as IRX4204 as taught by IO, above. LIBY further teaches, in mouse mammary tumor virus (MMTV)-neu mice, NRX194204 not only delayed the development of ER-negative mammary tumors but also caused marked tumor regression (92%) or growth arrest (8%) in all of the mammary tumors when used therapeutically (Pg. 6237 Abstract). LIBY teaches in MMTV-neu mice, wild-type neu is expressed in the mammary tissue under control of the MMTV promotor and ER- mammary tumors begin to appear (Pg. 6240 Right Col. P2). The Examiner understands the neu mammary tumors of LIBY to be an equivalent of HER2+, as evidenced by NCI. NCI discloses HER2/neu is a protein involved in cell growth and is found in breast cancer cells (Line 1). Thus, HER2 and neu are understood to reference the same protein.
MITRI teaches HER2 overexpression is present in approximately 20-30% of breast cancer tumors and is associated with a more aggressive disease, higher recurrence rate, and shortened survival (Pg. 1 Introduction P1). MITRI teaches trastuzumab is the standard of care in treatment of HER2+ breast cancer (Pg. 2 Sect. 3 P1). MITRI further teaches the ideal timing of trastuzumab administration appears to be concurrent with chemotherapy (Pg. 2 Sect. 3 P2). Examiner, thus, understands trastuzumab can be administered with another anti-cancer therapeutic. MITRI also teaches despite the success of Trastuzumab-based therapy in treating all stages of HER2+ breast cancer, resistance to Trastuzumab is an important issue which affects outcomes for a subset of patients (Pg 3 Sect. 5 P1).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
IO does not teach the breast cancer is HER2+ or that the additional anti-cancer agent is trastuzumab.
LIBY, evidenced by NCI, does not teach the method of treating HER2+ breast cancer further comprises administration of thyroxine and a HER2-targeted therapeutic such as trastuzumab.
MITRI does not teach a method of treating HER2+ breast cancer by administering IRX4204 and thyroxine.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of HER2+ breast cancer and possesses the technical knowledge necessary to make adjustments to the method to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding treatment of HER2+ breast cancer and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references IO, LIBY evidenced by NCI, and MITRI.
The artisan would be motivated to utilize the method of IO to treat HER2+ breast cancer in order to improve treatment outcomes and cause marked tumor regression or tumor growth arrest in the patient, in view of LIBY and MITRI. The artisan would recognize IRX4204/NRX194204 as suitable for treatment of HER2+ breast cancer since LIBY teaches 92% marked tumor regression and 8% growth arrest in a HER2/neu mouse model of breast cancer (Pg. 6237 Abstract). The artisan would be further motivated to treat HER2+ patients since MITRI teaches HER2+ breast cancer is associated with more aggressive disease (Pg. 1 Introduction P1); thus, the artisan would recognize the need for an improved treatment and in view of IO and LIBY be motivated to treat the HER2+ breast cancer with the combination IRX4204 and thyroxine. Moreover, IO teaches IRX4204 treats both ER-positive and -negative breast cancer cell lines with 74% efficacy in the ER-negative cell line (Pg. 26 Table 3). Thus, the artisan would recognize the efficacy of IRX4204 in treating non-hormone dependent breast cancer, i.e., a group which includes HER2+ breast cancer. Finally, the artisan would be motivated to utilize the combination IRX4204 and thyroxine since IO teaches optimal anti-cancer activity from combination administration of an RXR agonist and thyroid hormone (Pg. 2 P5) wherein thyroxine is preferred (Pg. 33 claim 7).
The artisan would be motivated to utilize this treatment in a patient receiving (instant claims 1 and 9)/undergoing treatment with (instant claim 5) a HER2-targeted therapeutic agent that is trastuzumab since MITRI teaches trastuzumab is the standard of care in treatment of HER2+ breast cancer (Pg. 2 Sect. 3 P1), but a subset of patients experience resistance to trastuzumab therapy (Pg 3 Sect. 5 P1). Thus, the artisan would recognize the need for an additional effective treatment in the case of “less than a complete response” (instant claim 5) to trastuzumab. The artisan would have an expectation of success since IO teaches the IRX4204/thyroxine treatment may be administered with another anti-cancer agent (Pg. 36 claim 29) and MITRI teaches the ideal timing of trastuzumab administration is concurrent with chemotherapy (Pg. 2 Sect. 3 P2).
Moreover, the artisan would have been imbued with at least a reasonable expectation of success that by combining IRX4204 and thyroxine with trastuzumab, one would have achieved a composition useful for treating HER2+ breast cancer since both are taught by the prior art as suitable for such treatment (see all teachings above). See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two agents each of which is taught by the prior art to be useful for the very same purpose. The idea of combining the two agents flows logically from having been individually taught in the prior art.
Thus, the artisan would find the instant claims 1-3, 5-7, 9-10, and 12-14 obvious.
Claims 1, 5, 9, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over IO (WO 2017/075612, filed in IDS of 06/19/2022), LIBY (Liby, K., et al., Cancer Susceptibility and Prevention, 2007, 13(20), 6237-6243, filed in IDS of 06/19/2022), as evidenced by NCI (National Cancer Institute, NCI Dictionary of Cancer Terms, “Her2/neu,” archived on Wayback Machine 04/23/2008, retrieved from https://web.archive.org/web/20180423100811/https://www.cancer.gov/publications/dictionaries/cancer-terms/def/her2-neu on 06/23/2025), and MITRI (Mitri, Z., et al., Chemotherapy Research and Practice, 2012, 2012,1-7) as applied to claims 1, 5, and 9 above, and further in view of ROMOND (Romond, E.H., et al., N. Engl. J. Med., 2005, 353(16), 1673-1684). These references were previously provided by Examiner (07/02/2025).
Determining the Scope and Contents of the Prior Art:
IO, LIBY evidenced by NCI, and MITRI teach the limitations of claims 1, 5, and 9, see above 103 rejection, paragraph 25.
LIBY teaches doses of 30 and 60 mg/kg diet for IRX4204 (Pg. 6242 Table 2).
ROMOND teaches trastuzumab is dosed at 2-4 mg/kg of body weight when administered with another chemotherapy (Pg. 1675 Left Col. P2) to patients with HER2+ breast cancer (Pg. 1673 Abstract Background).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
IO, LIBY evidenced by NCI, and MITRI do not teach the combination treatment of IRX4204 and trastuzumab is synergistic.
ROMOND does not teach the compound of Formula (I).
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of HER2+ breast cancer and possesses the technical knowledge necessary to make adjustments to the method to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding treatment of HER2+ breast cancer and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references IO, LIBY evidenced by NCI, MITRI, and ROMOND.
The claims 15-17 recite the combination of the HER2-targeteted therapeutic and the RXR agonist of Formula (I) results in greater inhibition of tumor growth compared to the additive effects of each of the agents alone. The Examiner understands these claims as being drawn to synergism between the two agents when co-administered.
Thus, the claims 15-17 are drawn to properties of the claimed combination treatment, i.e., the combined administration of the compound of Formula (I) and the HER2-targeted therapeutic agent is synergistic in nature. MPEP 2112.01.II states: “‘Products of identical chemical composition cannot have mutually exclusive properties.’ In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Since the references applied to claims 1, 5, and 9, above, teach both IRX4204 and trastuzumab and their suitability in treatment of HER2+ breast cancer, and the combination treatment of the two is found to be obvious, it would be expected that the combination would have the same physical properties as the combination in the instant application, namely that the combination exhibits synergy.
Furthermore, the Examiner understands this synergy to be a product of the dosages at which the two agents are given. See, for example, Pg. 36 paragraph 145 and Pg. 37 Table 1 of the instant specification, wherein certain concentrations of the two agents, when used together, were synergistic. The determination of the optimum dosages for both IRX4204 and trastuzumab would have been well within the practice of the artisan. The artisan would be motivated to optimize the dosages using the teachings of LIBY and ROMOND as starting points.
MPEP 2144.05(II)(A) provides guidance about the obviousness of optimization of variables within prior art conditions or through routine experimentation: "Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).”
In the instant case, the dosages of IRX4204 and trastuzumab are analogous to the “concentration or temperature” recited in the MPEP since dosage is a result-effective variable, i.e. a variable that achieves a recognized result (e.g., treatment outcomes or %inhibition of tumor growth). Since LIBY teaches dosages of IRX4204 that result in regression and arrest of growth in a percentage of HER2+ tumors (Pg.6237 Abstract) and ROMOND teaches doses of trastuzumab in co-administration with another anti-cancer agent to treat HER2+ breast cancer (Pg. 1675 Left. Col. P2), the artisan would have been motivated to modify the dosages of IRX4204 and trastuzumab taught in these prior art references, so as to optimize the treatment outcomes from co-administration of these two agents. Therefore, the dosages that would provide synergistic inhibition of tumor growth would have been obvious to arrive at through routine experimentation. Furthermore, absent any evidence demonstrating a patentable difference from the prior art teachings and the criticality of any dosage that would impart synergy to the combination treatment, the determination of the optimum synergistic dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the artisan.
Double Patenting - Maintained
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 5-6, 9, and 12-17 are rejected on the ground of anticipatory nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,224,583. Although the claims at issue are not identical, they are not patentably distinct from each other.
Note: withdrawn claims 4, 8, and 11 would be rejected if not withdrawn. Further, the instant application is a CON of the application from which the reference Patent issued, thus, the safe harbor protection of 35 U.S.C. 121 does not apply.
Patent ‘583 claim 5 is drawn to a method of treating a patient with HER2+ breast cancer comprising administering the RXR agonist
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, i.e., IRX4204, and a small molecule HER2 kinase inhibitor including lapatinib (claim 6), neratinib (claim 7), and tucatinib (claim 8). The recited species are species of the instant claims 1-2, 9, 12, and 14 and Patent claim 1 is also anticipatory in view of these species recited in Patent claims 5-8. Patent claim 3 is drawn to the method of treatment further comprising administering thyroid hormone. Patent claim 9 is drawn to the method of treatment wherein the inhibition of tumor cell growth by the combination of the HER2 kinase inhibitor and the RXR agonist is greater than additive effects of each of the HER2 kinase inhibitor and the RXR agonist alone. In view of the recited species, Patent claim 3 is anticipatory of instant claims 12 and 14 and Patent claim 9 is anticipatory of instant claims 15 and 17.
Patent ‘583 claim 12 is drawn to a method of treating a patient with HER2+ breast cancer undergoing treatment with a small molecule HER2 kinase inhibitor wherein there is less than a complete response, comprising continuing treatment with the HER2 kinase inhibitor and initiating treatment with the RXR agonist IRX4204. Patent claims 13, 14, and 15 recite the HER2 kinase inhibitor is lapatinib, neratinib, and tucatinib, respectively. The recited species are species of instant claims 5-6, 13, and 16 and Patent claim 2 is also anticipatory in view of these species recited in Patent claims 12-15. Patent claim 10 is drawn to the method of treatment further comprising administering thyroid hormone. Patent claim 16 is drawn to the method of treatment wherein the inhibition of tumor cell growth by the combination of the HER2 kinase inhibitor and the RXR agonist is greater than additive effects of each of the HER2 kinase inhibitor and the RXR agonist alone. In view of the recited species, Patent claim 10 is anticipatory of instant claim 13 and Patent claim 16 is anticipatory of instant claim 16.
Claims 1-3, 5-7, 9-10, and 12-17 are rejected on the ground of anticipatory nonstatutory double patenting as being unpatentable over claims 1 of U.S. Patent No. 10,966,950. Although the claims at issue are not identical, they are not patentably distinct from each other.
Note: The instant application is a CON of application no. 17/123,347 (Patent 11,224,583) which was a DIV of application no. 16/898,230 (Patent 10,966,950). Since the instant application is one step removed from the divisional filing status (i.e., the instant app is not a DIV), the safe harbor protection of 35 U.S.C. 121 does not apply.
Patent ‘950 claims are drawn to a method of treating a patient with HER2+ breast cancer receiving a HER2-targeted therapeutic antibody comprising administering the RXR agonist IRX4204 (claims 1, 5-6, and 9) further comprising administration of the HER2-targeted therapeutic antibody (claim 2) and a thyroid hormone (claim 4); wherein the therapeutic antibody is trastuzumab (claim 7) or pertuzumab (claim 8). Patent ‘950 claim 16 is drawn to the method of treatment wherein the inhibition of tumor cell growth by the combination of the HER2-targeted antibody and the RXR agonist is greater than the additive effects of the two agents alone. The Patent ‘950 recites species of the instant claims (i.e., IRX4204 and trastuzumab/pertuzumab) within the same method of treating HER2+ breast cancer. Thus, the Patent claims 1-2, 4-9, and 16 anticipate the instant claims 1-3, 9-10, 12, 14-15, and 17.
Patent ‘950 claims 3, 10-15, and 17 mirror the limitations of Patent claims 1-2, 4-9, and 16, except that the method of treatment comprises treating a patient undergoing treatment with a HER2-targeted antibody wherein there is evidence of therapeutic effect that is less than a complete response, comprising continuing treatment with the HER2 antibody and initiating treatment with the RXR agonist IRX4204 (see patent claims 3 and 13). Since the Patent claims recite species of the instant claims (i.e., IRX4204 and trastuzumab/pertuzumab) within the same method of treating HER2+ breast cancer with “less than a complete response,” the Patent claims 3, 10-15, and 17 anticipate the instant claims 5-7, 13, and 16.
Claims 1-3, 5-7, 9-10, and 12-17 are rejected on the ground of anticipatory nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,998,521. Although the claims at issue are not identical, they are not patentably distinct from each other.
Note: withdrawn claims 4, 8, and 11 would be rejected if not withdrawn.
Patent ‘521 is drawn to a method of treating a patient with HER2+ breast cancer (claim 11) resistant to at least one HER2-targetted therapeutic agent, comprising administering the RXR agonist IRX4204 (claim 4) further comprising administering thyroid hormone (claim 3); wherein the HER2-targeted therapeutic agent is an anti-HER2 antibody (claim 5) such as trastuzumab or pertuzumab (claim 6), an antibody-drug conjugate (claim 7), or a HER2 kinase inhibitor (claim 8) chosen from a handful of examples including lapatinib (claims 9-10). Patent ‘521 claim 12 is drawn to the method wherein inhibition of tumor cell growth by the combination RXR and HER2-targeted therapeutic is greater than additive inhibitor effects of each alone. The recited species are species of the rejected instant claims and, thus, anticipate them. Patent claims 1-2 are also anticipatory in view of the above species.
Patent ‘521 claims 13-23 are drawn to the same species as the patent claims 1-12, but the method is drawn to treatment of a patient with HER2+ breast cancer (claim 22) wherein the patient is undergoing treatment with a HER2-targeted therapeutic agent and the cancer has become resistant to the HER2 therapeutic (claim 13).
The examiner understands resistance to the HER2 therapeutic to be indicative of “less than a complete response” (see instant claim 5). Thus, since species of the instant are recited in the same treatment context, the Patent claims anticipate the instant claims.
Claims 1-3, 5-7, 9-10, and 12-17 are provisionally rejected on the ground of anticipatory nonstatutory double patenting as being unpatentable over claim 1-20 of copending Application No. 18/649,476 (reference application, claims of 04/29/2024). Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claims are drawn to a method of treating HER2+ breast cancer (claim 9) comprising administering the RXR agonist IRX4204 (claim 3) wherein the cancer is resistant to at least one HER2-targeted therapeutic and the patient is receiving the HER2-targeted therapeutic (parent claim 1); wherein the HER2-targeteted therapeutic agent is an anti-HER2 antibody (claim 4) such as trastuzumab or pertuzumab (claim 5), an antibody-drug conjugate comprising an anti-HER2 antibody (claim 6), or a HER2 kinase inhibitor (claim 7) chosen from a handful including lapatinib (claim 8). Reference claim 10 is drawn to the method wherein inhibition of tumor cell growth by the combination RXR and HER2-targeted therapeutic is greater than additive inhibitor effects of each alone. The recited species are species of the rejected instant claims and, thus, anticipate them. The examiner understands resistance to the HER2 therapeutic to be indicative of “less than a complete response” (see instant claim 5).
Reference claims 11-20 are drawn to the same species as the reference claims 1-10, but the method is drawn to treatment of a patient with HER2+ breast cancer (claim 19) wherein the patient is undergoing treatment with a HER2-targeted therapeutic agent and the cancer has become resistant to the HER2 therapeutic (claim 11).
Thus, since species of the instant are recited in the same treatment context, the Reference claims anticipate the instant claims.
Claims 1-3, 5-7, 9-10, and 12-14 are rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 1, 4-5, 9, and 11 of U.S. Patent No. 11,896,558 in view of MITRI (Mitri, Z., et al., Chemotherapy Research and Practice, 2012, 2012,1-7) as applied to claims 1-3, 5-7, 9-10, and 12-14 in the above 103 rejection.
Determining the Scope and Contents of the Prior Art:
Patent ‘558 claims are drawn to a method of treating a HER2+ cancer in a patient (claim 1) comprising administering the RXR agonist IRX4204 (claim 5) further comprising administering thyroid hormone (claim 4); wherein the HER2+ cancer is breast cancer (claim 9). Patent ‘558 claim 11 is drawn to the method of patent claim 1 further comprising administration of an additional anticancer agent.
The teachings MITRI are above in paragraph 25.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
Patent ‘558 does not teach wherein the additional anticancer agent is a HER2-targeted therapeutic such as trastuzumab, wherein there is evidence of therapeutic effects that is less than a complete response in a patient receiving the trastuzumab.
MITRI is not a U.S. Patent document.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of HER2+ breast cancer and possesses the technical knowledge necessary to make adjustments to the method to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding treatment of HER2+ breast cancer and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references U.S. Patent 11,896,558 and MITRI.
The main motivation to treat a patient that is receiving trastuzumab and may have “less than a complete response” to the trastuzumab therapy comes from MITRI: trastuzumab is the standard of care in treatment of HER2+ breast cancer (Pg. 2 Sect. 3 P1), but a subset of patients experience resistance to trastuzumab therapy (Pg 3 Sect. 5 P1). The artisan would have an expectation of success since Patent ‘558 discloses the compound IRX4204 and thyroid hormone may be administered with an additional anti-cancer agent in a method of treating HER2+ breast cancer (see all teachings above).
Claims 1-3, 5-7, 9-10, and 12-14 are rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 1, 6, 8-10, and 15 of U.S. Patent No. 10,973,788 in view of IO (WO 2017/075612, cited in IDS of 06/19/2022), LIBY (Liby, K., et al., Cancer Susceptibility and Prevention, 2007, 13(20), 6237-6243), as evidenced by NCI (National Cancer Institute, NCI Dictionary of Cancer Terms, “Her2/neu,” archived on Wayback Machine 04/23/2008, retrieved from https://web.archive.org/web/20180423100811/https://www.cancer.gov/publications/dictionaries/cancer-terms/def/her2-neu on 06/23/2025), and MITRI (Mitri, Z., et al., Chemotherapy Research and Practice, 2012, 2012,1-7) as applied to claims 1-3, 5-7, 9-10, and 12-14 in the above 103 rejection.
Determining the Scope and Contents of the Prior Art:
Patent ‘788 claims are drawn to a method of treating cancer in a patient comprising administering the RXR agonist IRX4204 (claim 1 and 15) further comprising treating the patient with an anti-cancer agent (claim 6) that is a monoclonal antibody (claim 8) and a TSH modulating agent (claim 9) that is a thyroid hormone (claim 10).
The disclosure of Patent ‘788 is referred to in order to understand what cancers are treated by the claimed method, in accordance with MPEP 804(II)(B)(1): “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970).” The disclosure Example 4 teaches VTP194204 (i.e., IRX4204) exhibited tumor growth inhibitory effects in breast cancer (Pg. 23 Col. 27 Ex. 4).
The IO, LIBY evidenced by NCI, and MITRI teachings are above, paragraph 25.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
Patent ‘788 does not teach wherein the breast cancer is HER2+, the additional anticancer agent monoclonal antibody is trastuzumab, there is evidence of therapeutic effect that is less than a complete response in a patient receiving the trastuzumab, and the thyroid hormone is thyroxine.
IO, LIBY evidenced by NCI, and MITRI are not U.S. Patent documents.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of HER2+ breast cancer and possesses the technical knowledge necessary to make adjustments to the method to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding treatment of HER2+ breast cancer and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references U.S. Patent 10,973,788, IO, LIBY evidenced by NCI, and MITRI.
Since Patent ‘788 teaches the administration of IRX4204 to a patient having breast cancer further comprising administration of an additional anti-cancer agent and a thyroid hormone, i.e., the same context in which IRX4204 is taught to be useful by IO, the artisan would find the instant claims obvious and be motivated to practice the instant method by the same logic as laid out in the above 103 rejection, paragraph 25.
The main motivation, with an expectation of success to include thyroxine as the thyroid hormone comes from IO: RXR activation by an RXR agonist gives optimal anti-cancer activity when combined with administration of a thyroid hormone (Pg. 2 P5) and the thyroid hormone is thyroxine (Pg. 33 claim 7).
The artisan would be motivated with an expectation of success to treat HER2+ breast cancer in view of LIBY: IRX4204 delayed the development of tumors, caused marked tumor regression (92%), and growth arrest (8%) in a mouse model of HER2/neu breast cancer (Pg. 6237 Abstract).
The main motivation, with an expectation of success, to treat a patient that is receiving trastuzumab and may have “less than a complete response” to the trastuzumab therapy comes from MITRI: trastuzumab is the standard of care in treatment of HER2+ breast cancer (Pg. 2 Sect. 3 P1), but a subset of patients experience resistance to trastuzumab therapy (Pg 3 Sect. 5 P1).
Claims 1-3, 5-7, 9-10, and 12-14 are rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 1, 6, and 10 of U.S. Patent No. 9,655,872 in view of IO (WO 2017/075612, filed in IDS of 06/19/2022), LIBY (Liby, K., et al., Cancer Susceptibility and Prevention, 2007, 13(20), 6237-6243, filed in IDS of 06/19/2022), as evidenced by NCI (National Cancer Institute, NCI Dictionary of Cancer Terms, “Her2/neu,” archived on Wayback Machine 04/23/2008, retrieved from https://web.archive.org/web/20180423100811/https://www.cancer.gov/publications/dictionaries/cancer-terms/def/her2-neu on 06/23/2025), and MITRI (Mitri, Z., et al., Chemotherapy Research and Practice, 2012, 2012,1-7) as applied to claims 1-3, 5-7, 9-10, and 12-14 in the above 103 rejection.
Determining the Scope and Contents of the Prior Art:
Patent ‘872 claims are drawn to a method of treating breast cancer in a patient comprising administering the RXR agonist IRX4204 (claim 1 and 10) further comprising treating the patient with at least one other agent selected from anti-cancer agents and TSH modulating agents (claim 6).
The IO, LIBY evidenced by NCI, and MITRI teachings are above, paragraph 25.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
Patent ‘872 does not teach wherein the breast cancer is HER2+, the additional anticancer agent is a HER2-targeted therapeutic trastuzumab, there is evidence of therapeutic effect that is less than a complete response in a patient receiving the trastuzumab, and the TSH modulator is thyroxine.
IO, LIBY evidenced by NCI, and MITRI are not U.S. Patent documents.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treatment of HER2+ breast cancer and possesses the technical knowledge necessary to make adjustments to the method to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding treatment of HER2+ breast cancer and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references U.S. Patent 9,655,872, IO, LIBY evidenced by NCI, and MITRI.
Since Patent ‘872 teaches the administration of IRX4204 to a patient having breast cancer further comprising administration of additional anti-cancer agents and TSH modulators, i.e., the same context in which IRX4204 is taught to be useful by IO, the artisan would find the instant claims obvious and be motivated to practice the instant method by the same logic as laid out in the above 103 rejection, paragraph 25.
The main motivation, with an expectation of success to include thyroxine as the TSH modulator comes from IO: RXR activation by an RXR agonist gives optimal anti-cancer activity when combined with administration of a thyroid hormone (Pg. 2 P5) and the thyroid hormone is thyroxine (Pg. 33 claim 7).
The artisan would be motivated with an expectation of success to treat HER2+ breast cancer in view of LIBY: IRX4204 delayed the development of tumors, caused marked tumor regression (92%), and growth arrest (8%) in a mouse model of HER2/neu breast cancer (Pg. 6237 Abstract).
The main motivation, with an expectation of success, to treat a patient that is receiving trastuzumab and may have “less than a complete response” to the trastuzumab therapy comes from MITRI: trastuzumab is the standard of care in treatment of HER2+ breast cancer (Pg. 2 Sect. 3 P1), but a subset of patients experience resistance to trastuzumab therapy (Pg 3 Sect. 5 P1).
Conclusion
Claims 1-3, 5-7, 9-10, and 12-17 are rejected.
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.
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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