DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Applicant's reply filed on 10/6/2025 is acknowledged. New claim 35 has been added. Claims 13-35 are pending. Claims 1-12 are canceled. Claims 32-34 are withdrawn from consideration. Claims 13-14, 16-28, 30-32 and 34 have been amended.
3. Claims 13-31 and 35 are under examination.
Rejections Withdrawn
4. The rejection of claim 17 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of applicant’s amendments.
5. The rejection of claims 13-29 and 31 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of applicant’s amendments.
6. The rejection of claims 13-29 and 31 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating cancer in a subject comprising administering to the subject a recombinant soluble human LAG-3Ig (IMP321), does not reasonably provide enablement for a method of treating cancer in a subject comprising administering to the subject any derivatives of LAG-3 is withdrawn in view of applicant’s amendments.
Rejections Maintained
Claim Rejections - 35 USC § 103
7. 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.
8. Claims 13-25, 27, 29-31, and new claim 35 remain/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Clinical Trial Study NCT00349934 (version 1, first posted on 7/10/2006, IDS filed on 1/18/2023), in view of Hortobagyi (Semin Oncol, 2001, 28(suppl 18):43-47).
Regarding claims 13, 15-20, 24-25, 27, 30, 31 and new claim 35, NCT00359943 (version 1) discloses IMP321 (recombinant soluble LAG-3-Ig fusion protein) phase I study in metastatic breast carcinoma patients (human subjects), the study is performed with patients receiving as a first line chemotherapy for metastatic breast carcinoma the standard 6 cycles of paclitaxel (80 mg/m2 at day 1, 8 and 15 of a 4-week cycle). IMP321 at a dose of 250 or 1,250 µg (1.25mg) is subcutaneously administered to the patients one dose every two weeks for a total of 24 weeks, separated by 13-day intervals free of IMP321 administration, on day 2 and 16 of the 4-week cycles, on the day which follows chemotherapy (i.e. about 24 hours after chemotherapy) (under Study Description). No additional antigen is administered to the patients in the method of .
IMP321 (which binds MHC class II molecule) at a dose of 1.25 mg is capable of inducing a systemic increase in the number of monocytes in blood of the subject and eliciting a systemic monocyte-mediated immune response, as evidenced by the instant specification (see Example 1, 0.25 mg IMP321 induced systemic increase in the number of monocytes in blood of breast cancer patients and elicited a systemic monocyte-mediated immune response).
NCT00359943 (version 1) does not disclose treating the metastatic breast cancer with trastuzumab.
Hortobagyi teaches that that as a single agent, trastuzumab has substantial and reproducible antitumor activity in HER2/neu-amplified metastatic breast cancer. In addition, when added to chemotherapy, trastuzumab improves antitumor efficacy as measured by time to progression, response rate, and survival (abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have modified the method of NCT00359943 (version 1) to further treat the metastatic breast cancer with trastuzumab in view of Hortobagyi. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Hortobagyi teaches that as a single agent, trastuzumab has substantial and reproducible antitumor activity in HER2/neu-amplified metastatic breast cancer. In addition, when added to chemotherapy, trastuzumab improves antitumor efficacy as measured by time to progression, response rate, and survival (abstract).
Both IMP321 and trastuzumab were used in the art for treating metastatic breast cancer. One of ordinary skill in the art would have combined them to treat metastatic breast cancer. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960).
Moreover, it was known in the art that drug combinations produce higher rates of objective response and longer survival than single agents because it combines two anti-cancer agents, each operating via a different mechanism of action, and as such it could solve problems arising in the clinic, such as the development of resistance to drugs.
Regarding claim 14, when IMP321 and trastuzumab are used together to treat metastatic breast cancer, they would have been administered simultaneously, separately or sequentially.
Regarding claims 21-23, the cited references do not specifically teach that IMP321 is administered subsequent to the administration of trastuzumab, one or two days after the administration of trastuzumab, and 12 to 96 hours after the administration of trastuzumab. This amounts to no more than routine optimization which would be performed by one of ordinary skill in this art. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). Absent unexpected results, it would have been prima facie obvious to one of ordinary skill at the time of invention to attempt different administration regimes, including administering IMP321 one or two days after administration of trastuzumab. One of ordinary skill in the art would find it obvious because the administration of drug can often precede or follow the administration of another drug, as part of a optimization method.
Applicant’s Arguments
The response states that Study 1 does not teach or suggest treating any cancer through the administration of IMP321 in combination with a therapeutic antibody, as Applicant claims. Instead, Study 1 merely describes plans to conduct experiments of a combination of IMP321 and a chemotherapy. While Hortobagyi may disclose the combination of trastuzumab alone or in addition to chemotherapy, Hortobagyi does not teach or suggest the use of trastuzumab in addition to another antibody treatment, let alone a recombinant soluble human LAG-3Ig fusion protein. As such, not every element of Applicant's claims are taught or suggested by the combination of Study 1 and Hortobagyi. Without the teaching or suggestion of all the components of amended claim 13, the rejection of claim 13 under 35 U.S.C. §103 is improper.
Additionally, there is no motivation for one of skill in the art to combine Study 1 with Hortobagyi to arrive at Applicant's amended claim 13, nor any reasonable expectation of success even if such an attempt had been made. The purpose of Study 1 is the planning of a dose-escalation study for IMP321 carried out on subjects receiving the "standard 6 cycles of weekly paclitaxel" as a first line chemotherapy for metastatic breast carcinoma. Thus, the focus of the document is a plan for a safety dose-finding for IMP321 administered to subjects on standard chemotherapy treatment. Study 1 does not describe, teach, or suggest any results of the combination therapy involving IMP321 and chemotherapy (80 mg/m2 paclitaxel); therefore, Study 1 does not teach or suggest whether such combination is safe, or the surprising technical effect of the invention (a systemic increase in the number of monocytes in the blood). Thus, Study 1 does not contain any disclosure of the results of actual administration of 250 pg or 1,250 pgIM1P321; rather, Study 1 is merely a plan to conduct a safety dose- escalation study of IMP321 in combination with paclitaxel, a chemotherapy. There is no teaching or suggestion in this document of any dose of IMP321 that is safe or effective in the treatment of cancer in metastatic breast carcinoma patients receiving chemotherapy, let alone a teaching or suggestion of any dose of IMP321 that is safe or effective in the treatment of cancer in combination with an additional therapeutic antibody. Hortobagyi is directed solely at the anti-tumor effects of Trastuzumab alone, or Trastuzumab in combination with chemotherapy. Study 1 combines soluble IMP321 fusion protein with a chemotherapy while Hortobagyi combines an antibody therapy with a chemotherapy; they do not teach or suggest the combination of a fusion protein with an antibody. Therefore, there is no reason why the skilled person would combine Hortobagyi with Study 1.
Lastly, the Office alleges that IMP321 "is capable of inducing a systemic increase in the number of monocytes in blood of the subject and eliciting a systemic monocyte-mediated immune response, as evidenced by the instant specification". Office Action, p. 13. However, it is improper to use the Applicant's specification to determine motivation.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive. Study 1 teaches treating metastatic breast cancer with soluble IMP321 fusion protein and a chemotherapy. Hortobagyi teaches treating metastatic breast cancer with trastuzumab (a therapeutic antibody) and a chemotherapy. Both IMP321 and trastuzumab were used in the art for treating metastatic breast cancer and both can be combined with chemotherapy. One of ordinary skill in the art would have combined them to treat metastatic breast cancer. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960). Moreover, it was known in the art that drug combinations produce higher rates of objective response and longer survival than single agents because it combines two anti-cancer agents, each operating via a different mechanism of action, and as such it could solve problems arising in the clinic, such as, the development of resistance to drugs. Therefore, the combination of Study and Hortobagyi teaches a combined therapy of IMP321 and trastuzumab. Study 1 teaches that the dose of IMP321 is 250 or 1,250 µg (1.25mg). IMP321 (which binds MHC class II molecule) at a dose of 1.25 mg is capable of inducing a systemic increase in the number of monocytes in blood of the subject and eliciting a systemic monocyte-mediated immune response, as evidenced by the instant specification (see Example 1, 0.25 mg IMP321 induced systemic increase in the number of monocytes in blood of breast cancer patients and elicited a systemic monocyte-mediated immune response). Here applicant’s specification is used by the examiner to show the inherent property of 1.25 mg IMP321, not to determine motivation. Furthermore, the property of being able to induce a systemic monocyte-mediated immune response is a property of IMP321, not an unexpected results from combination with a therapeutic antibody.
Applicant’s arguments of no reasonable expectation of success are not persuasive. MPEP 2143.02 [R-6] II states “Obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). In the instant case, both IMP321 and trastuzumab were used individually in the art to treat metastatic breast cancer and both can be combined with chemotherapy. One of ordinary skill in the art would have had a reasonable expectation of success to treat same cancer with both drugs. Moreover, MPEP 2121 III states that efficacy is not a requirement for prior art enablement.
For the foregoing reasons, the rejection is maintained.
9. Claims 13-31 and new claim 35 remain/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Clinical Trial Study NCT00349934 (version 1, first posted on 7/10/2006, IDS filed on 1/18/2023), in view of Hortobagyi (Semin Oncol, 2001, 28(suppl 18):43-47), further in view of Clinical Trial Study NCT00351949 (version 2, posted on 10/23/2006, IDS filed on 1/18/2023).
The teachings of NCT00359943 (version 1) and Hortobagyi have been set forth above as they apply to claims 13-25, 27, 29-31 and new claim 35.
Regarding claims 26 and 28, NCT00359943 (version 1) and Hortobagyi do not disclose a dose of IMP321 that is higher than 6 mg.
NCT00351949 (version 2) discloses a method of treating metastatic renal cell carcinoma in a human patient, the method comprising subcutaneously administering to the patient 6.25 mg IMP321 every 2 weeks for a total of 12 weeks, separated by 13 day administration free intervals (page 3).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have modified the method of NCT00359943 (version 1) to use 6.25 mg IMP321 in view of NCT00351949 (version 2). One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because NCT00351949 (version 2) discloses that 6.25 mg IMP321 can be used in treating human patients having metastatic renal cell carcinoma.
Applicant’s Arguments
The response states that Office alleges that Study 2 discloses a method of treating metastatic renal cell carcinoma in a human patient, the method comprising subcutaneously administering to the patient 6.25 mg IMP321 every two weeks for a total of 12 weeks. The deficiencies of Study 1 and Hortobagyi are discussed above. The inclusion of a dose of 6.25mg IMP321 does not rectify those deficiencies. As such, the combination of Study 1, Hortobagyi, and Study 2 does not teach or suggest a method of treating cancer in a human subject through the administration of an effective amount of a therapeutic antibody and "a recombinant soluble human LAG-3Ig fusion protein comprising at least the first and second immunoglobulin-like domains of the native human LAG-3 protein fused to human IgG1 Fc; wherein the recombinant soluble human LAG-3Ig fusion protein induces a systemic increase in the number of monocytes in blood of the subject, and elicits a systemic monocyte-mediated immune response. Nor does the combination of Study 1, Hortobagyi, and Study 2 provide any motivation to a person having ordinary skill in the art to arrive at the Applicant's claims with a reasonable expectation of success.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive for the same reasons as discussed above. Study 2 (NCT00351949 v.2) was cited by the examiner to show that 6.25 mg IMP321 can be used in treating human patients having metastatic renal cell carcinoma.
10. Claims 13-31 and new claim 31 remain/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Triebel (US 7,109,026B2, Date of Patent: 9/19/2006, IDS filed on 1/18/2023), as evidenced by 2005 FDA Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (IDS filed on 1/18/2023), in view of Clinical Trial Study NCT00349934 (version 1, first posted on 7/10/2006, IDS filed on 1/18/2023), and Sotomayor (Hematology, June 2007, 233-242).
Regarding claim 13, Triebel teaches a method of treating a cancer in mice, the method comprising administering a soluble hLAG-3 to the mice, wherein the cancer is renal cell carcinoma, mammary adenocarcinoma, colon carcinoma or sarcoma (working examples)
Regarding claim 25, Triebel teaches that the soluble hLAG-3 is administered subcutaneously or intradermally (column 5, lines 42-23, 45-46, column 6, lines 1-3).
Regarding claims 26-28, Triebel teaches that systemic administration of soluble hLAG-3 directly induces an inhibition of in vivo tumor growth, the inhibition is dose dependent (column 3, lines 5-6, Example IV and Fig.6). Fig. 6 shows that a dose of 250 µg was more effective in inhibition of tumor growth than a dose of 25 µg (Example IV and Fig. 6). For a mouse dose of 25 µg and 250 µg (the average body weight of mice is 20 g), the human equivalent dose is 0.1 mg/kg and 1 mg/kg, respectively (calculated by multiplying the mouse dose by 0.08 according to Table 1 of 2005 FDA Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, reproduced below). For human subjects having an average body weight of 60 Kg, the dose would be 6 mg and 60 mg respectively. Triebel teaches that by using an ELISA assay, high concentrations (about 1 ng/ml) of soluble LAG-3 were found in blood of patients with cancer (column 11, lines 33-35).
Triebel does not specifically teach treating cancer in human subjects and does not teach treating B-cell lymphoma. However, Triebel teaches that LAG-3 expression on TILs (tumor infiltrating lymphocytes) was detected in all samples tested, including melanoma, renal cell adenocarcinomas and B-cell lymphoma (Example 5).
NCT00359943 (version 1) discloses IMP321 (recombinant soluble LAG-3-Ig fusion protein) phase I study in metastatic breast carcinoma patients (human subjects), the study is performed with patients receiving as a first line chemotherapy for metastatic breast carcinoma the standard 6 cycles of paclitaxel (80 mg/m2 at day 1, 8 and 15 of a 4-week cycle). Regarding claims 16-20, NCT00359943 (version 1) teaches that IMP321 at a dose of 250 or 1,250 µg (1.25mg) is subcutaneously administered to the patients one dose every two weeks for a total of 24 weeks, separated by 13-day intervals free of IMP321 administration, on day 2 and 16 of the 4-week cycles, on the day which follows chemotherapy (i.e. about 24 hours after chemotherapy) (under Study Description).
IMP321 (which binds MHC class II molecule) at a dose of 1.25 mg is capable of inducing a systemic increase in the number of monocytes in blood of the subject and eliciting a systemic monocyte-mediated immune response, as evidenced by the instant specification (see Example 1, 0.25 mg IMP321 induced systemic increase in the number of monocytes in blood of breast cancer patients and elicited a systemic monocyte-mediated immune response).
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It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have treated cancer including B cell lymphoma in human patients with soluble hLAG-3 or IMP321 in view of Triebel and NCT00359943 (version 1). One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Triebel has shown that systemic administration of soluble hLAG-3 directly induced an inhibition of different types of cancers and teaches that LAG-3 expression on TILs (tumor infiltrating lymphocytes) was detected in all samples tested, including B-cell lymphoma (Example 5) and NCT00359943 (version 1) teaches treating human subjects having breast cancer with IMP321.
Triebel and NCT00359943 (version 1) do not teach further treating B-cell lymphoma with rituximab.
Sotomayor teaches that rituximab either alone or more effectively in combination with chemotherapy has dramatically changed our therapeutic approach to patients with almost every type of B cell lymphoma (page 240, column 2).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have combined soluble hLAG-3 (or IMP321) and rituximab to treat B cell lymphoma in view of Triebel, NCT00359943 (version 1) and Sotomayor. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Sotomayor teaches treating B-cell lymphoma with rituximab.
Both rituximab and hLAG-3 (or IMP321) were taught in the art to treat B cell lymphoma. One of ordinary skill in the art would have combined them to treat B cell lymphoma. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960).
Moreover, it was known in the art that drug combinations produce higher rates of objective response and longer survival than single agents because it combines two anti-cancer agents, each operating via a different mechanism of action, and as such it could solve problems arising in the clinic, such as, the development of resistance to drugs.
Regarding claim 14, when IMP321 and rituximab are used together to treat B cell lymphoma, they would have been administered simultaneously, separately or sequentially.
Regarding claims 21-23, the cited references do not specifically teach that hLAG-3 (or IMP321) is administered subsequent to the administration of rituximab, one or two days after the administration of rituximab, and 12 to 96 hours after the administration of rituximab. This amounts to no more than routine optimization which would be performed by one of ordinary skill in this art. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). Absent unexpected results, it would have been prima facie obvious to one of ordinary skill at the time of invention to attempt different administration regimes, including administering hLAG-3 (or IMP321) one or two days after administration of rituximab. One of ordinary skill in the art would find it obvious because the administration of drug can often precede or follow the administration of another drug, as part of a optimization method.
Applicant’s Arguments
The response states that Study 1 does not teach or suggest all aspects of Applicant's amended independent claims 13 and 31. Specifically, Study 1 does not teach or suggest treating any cancer through the administration of IMP321 in combination with a therapeutic antibody, as claimed. Instead, Study 1 merely describes plans to conduct experiments of a combination of IMP321 and a chemotherapy.
Triebel does not rectify this deficiency as Triebel is silent regarding a therapeutic antibody or chemotherapy. There is no teaching or suggestion that IMP321 could or should be used in combination with another therapy. As such, the combination of Triebel and Study 1 does not teach or suggest treating any cancer through the administration of IMP321 in combination with a therapeutic antibody, as claimed.
The Office looks to Sotomayor to rectify the deficiencies of Triebel and Study 1. However, as with Hortobagyi above, Sotomayor is directed to the use of an antibody in combination with a chemotherapy. As such, Sotomayor does not teach or suggest treating any cancer through the administration of IMP321 in combination with a therapeutic antibody, as claimed.
Consequently, Applicant respectfully submits that the combination of Triebel, Study 1, and Sotomayor does not teach treating any cancer through the administration of IMP321 in combination with a therapeutic antibody, as claimed.
Additionally, for the same reasons as argued above, Applicant submits that there is no motivation for one of skill in the art to combine Triebel, Study 1, and Sotomayor to arrive at Applicant's amended independent claim 13 or 31, nor is there any reasonable expectation of success even if such an attempt had been made.
Without the requisite motivation, Applicant's amended claims cannot be obvious over the combination of Triebel, Study 1, and Sotomayor under 35 U.S.C. §103. Consequently, Applicant respectfully requests that the rejection of claims 13-31 under 35 U.S.C. §103 be withdrawn.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive Triebel teaches a method of treating a cancer in mice using a soluble hLAG-3 to the mice, wherein the cancer is renal cell carcinoma, mammary adenocarcinoma, colon carcinoma or sarcoma (working examples). Triebel further teaches that LAG-3 expression on TILs (tumor infiltrating lymphocytes) was detected in all samples tested, including melanoma, renal cell adenocarcinomas and B-cell lymphoma (Example 5).
Although Triebel does not specifically teach treating cancer including B-cell lymphoma in human subjects. NCT00359943 (version 1) provides evidence that IMP321 (recombinant soluble LAG-3-Ig fusion protein) can be used to treat human cancer patients. It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have treated cancer including B cell lymphoma in human patients with soluble hLAG-3 or IMP321 in view of Triebel and NCT00359943 (version 1). One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Triebel has shown that systemic administration of soluble hLAG-3 directly induced an inhibition of different types of cancers and teaches that LAG-3 expression on TILs (tumor infiltrating lymphocytes) was detected in all samples tested, including B-cell lymphoma (Example 5) and NCT00359943 (version 1) teaches treating human subjects having breast cancer with IMP321.
Sotomayor teaches that rituximab either alone or more effectively in combination with chemotherapy has dramatically changed our therapeutic approach to patients with almost every type of B cell lymphoma (page 240, column 2).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have combined soluble hLAG-3 (or IMP321) and rituximab to treat B cell lymphoma in view of Triebel, NCT00359943 (version 1) and Sotomayor. Both rituximab and hLAG-3 (or IMP321) were taught in the art to treat B cell lymphoma. One of ordinary skill in the art would have combined them to treat B cell lymphoma. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Moreover, it was known in the art that drug combinations produce higher rates of objective response and longer survival than single agents because it combines two anti-cancer agents, each operating via a different mechanism of action, and as such it could solve problems arising in the clinic, such as, the development of resistance to drugs.
Applicant’s arguments of no reasonable expectation of success are not persuasive. MPEP 2143.02 [R-6] II states “Obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). In the instant case, both IMP321 (soluble hLAG-3 protein) and rituximab were used in the art to treat cancer. Triebel has shown that a soluble hLAG-3 is effective in treating renal cell carcinoma, mammary adenocarcinoma, colon carcinoma or sarcoma in animal model (working examples). NCT00359943 (version 1) provides evidence that IMP321 (recombinant soluble LAG-3-Ig fusion protein) can be used to treat human cancer patients. One of ordinary skill in the art would have had a reasonable expectation of success to treat cancer with both drugs.
For the foregoing reasons, the rejection is maintained.
Double Patenting
11. 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
12. Claims 13-31 and new claim 35 remain/are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,583,582, in view of Hortobagyi (Semin Oncol, 2001, 28(suppl 18):43-47).
Claims 1-11 of U.S. Patent No. 11,583,582 disclose a method of treating cancer in a human subject in need thereof, which comprises: administering to the subject an effective amount of: (i) a chemotherapy agent; and (ii) IMP321; wherein the IMP321 induces a systemic increase in the number of monocytes in blood of the subject, and elicits a systemic monocyte-mediated immune response; wherein the IMP321 is administered to the subject at a dose of more than 6 mg; and wherein the blood concentration of the IMP321 in the subject is greater than 1 ng/ml, for at least 24 hours after administration of the IMP321 to the subject,
wherein the chemotherapy agent and the IMP321 are administered to the subject simultaneously, separately, or sequentially, the IMP321 is administered 12 to 96 hours after administration of the chemotherapy agent, the subject is treated without administration of any additional antigen, the subject is administered an effective plurality of doses of the IMP321, the cancer is metastatic breast cancer or metastatic renal cell cancer, the IMP321 is administered to the subject at a dose of more than 6.25 mg, at a dose of about 30 mg.
The claims of the patent do not teach treating the subject with trastuzumab. However, these deficiencies are made up for in the teachings of Hortobagyi
The teachings of Hortobagyi have been set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have further treated the metastatic breast cancer with trastuzumab in view of Hortobagyi. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Hortobagyi teaches that as a single agent, trastuzumab has substantial and reproducible antitumor activity in HER2/neu-amplified metastatic breast cancer. In addition, when added to chemotherapy, trastuzumab improves antitumor efficacy as measured by time to progression, response rate, and survival (abstract).
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960).
Moreover, it was known in the art that drug combinations produce higher rates of objective response and longer survival than single agents because it combines two anti-cancer agents, each operating via a different mechanism of action, and as such it could solve problems arising in the clinic, such as the development of resistance to drugs
13. Claims 13-31 and new claim 35 remain/are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 10,232,038, in view of Clinical Trial Study NCT00349934 (version 1, first posted on 7/10/2006, IDS filed on 1/18/2023) and Hortobagyi (Semin Oncol, 2001, 28(suppl 18):43-47).
Claims 1-17 of U.S. Patent No. 10,232,038 disclose a method of treating cancer in a human subject in need thereof, which comprises: administering to the subject a chemotherapy agent, and an effective plurality of doses of a recombinant human LAG-3 protein, or a derivative thereof; inducing a systemic increase in the number of monocytes in blood of the subject; and eliciting a systemic monocyte-mediated immune response; wherein the subject is treated without administration of any additional antigen; and wherein the recombinant human LAG-3 protein comprises an extracellular region having the first, second, third and fourth immunoglobulin-like domains of a native human LAG-3 protein, and the derivative is IMP321, wherein the recombinant human LAG-3 protein, or derivative thereof, is administered to the subject before, with, or subsequent to, the administration of the chemotherapy agent, wherein a plurality of doses of the chemotherapy agent is administered to the subject, wherein a dose of the plurality of doses of the recombinant human LAG-3 protein, or derivative thereof, is administered to the subject subsequent to administration of each dose of the chemotherapy agent, wherein the recombinant human LAG-3 protein, or derivative thereof, is administered 12 to 96 hours after the administration of the chemotherapy agent, the chemotherapy agent is selected from the group consisting of taxanes, anthracyclines, and gemcitabine, the chemotherapy agent is paclitaxel.
Claims 1-17 of U.S. Patent No. 10,232,038 do not disclose treating metastatic breast cancer and do not disclose further treating breast cancer with trastuzumab. However, these deficiencies are made up for in the teachings of NCT00349934 (version 1) and Hortobagyi.
The teachings of NCT00349934 (version 1) and Hortobagyi have been set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have treated metastatic breast cancer with IMP321 in view of NCT00349934 (version 1) and Hortobagyi. One would have been motivated to do so with a reasonable expectation of success because the method of claims 1-17 of U.S. Patent No. 10,232,038 is for treating any cancer and NCT00349934 (version 1) teaches treating metastatic breast cancer with IMP321 combined with chemotherapy.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have further treated the metastatic breast cancer with trastuzumab in view of Hortobagyi. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Hortobagyi teaches that as a single agent, trastuzumab has substantial and reproducible antitumor activity in HER2/neu-amplified metastatic breast cancer. In addition, when added to chemotherapy, trastuzumab improves antitumor efficacy as measured by time to progression, response rate, and survival (abstract).
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960).
Moreover, it was known in the art that drug combinations produce higher rates of objective response and longer survival than single agents because it combines two anti-cancer agents, each operating via a different mechanism of action, and as such it could solve problems arising in the clinic, such as the development of resistance to drugs.
14. Claims 13-31 and new claim 35 remain/are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 9,579,382, in view of Clinical Trial Study NCT00349934 (version 1, first posted on 7/10/2006, IDS filed on 1/18/2023) and Hortobagyi (Semin Oncol, 2001, 28(suppl 18):43-47).
Claims 1-9 of U.S. Patent No. 9,579,382 disclose a method of treating cancer in a human subject in need thereof, which comprises: administering to the subject, by systemic administration, an effective plurality of doses of a recombinant human LAG-3 protein or a derivative thereof, wherein the recombinant human LAG-3 protein comprises an extracellular region having the first, second, third and fourth
immunoglobulin-like domains of a native human LAG-3 protein and the derivative
is IMP321; wherein the recombinant human LAG-3 protein or the derivative inducing systemic increase in the number of monocytes in blood of the subject; and eliciting a systemic monocyte-mediated immune response, wherein the subject is treated in the absence of any additional antigen, wherein each dose of the recombinant human LAG-3 protein or derivative thereof is 8-25 mg of the recombinant soluble human LAG-3Ig fusion protein IMP321, or a molar equivalent of 8-25 mg of IMP321, wherein one dose of the recombinant LAG-3 protein or derivative thereof is administered every one to several weeks for at least 12 weeks, separated by 13-day±2 days administration-free,
wherein each dose of the recombinant LAG-3 protein or derivative thereof is formulated so as to allow subcutaneous or intravenous administration, the plurality of doses include at least 6 doses, the plurality of doses are given on an every-two-week schedule, said at least 6 doses are given on an every-two-week schedule.
Claims 1-9 of U.S. Patent No. 9,579,382 do not teach treating metastatic breast cancer, and further treating the patients with trastuzumab. However, these deficiencies are made up for in the teachings of NCT00349934 (version 1) and Hortobagyi
The teachings of NCT00349934 (version 1) and Hortobagyi have been set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have treated metastatic breast cancer with IMP321 in view of NCT00349934 (version 1). One would have been motivated to do so with a reasonable expectation of success because the method of claims 1-17 of U.S. Patent No. 10,232,038 is for treating any cancer and NCT00349934 (version 1) teaches treating metastatic breast cancer with IMP321.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have further treated the metastatic breast cancer with trastuzumab in view of Hortobagyi. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Hortobagyi teaches that as a single agent, trastuzumab has substantial and reproducible antitumor activity in HER2/neu-amplified metastatic breast cancer. In addition, when added to chemotherapy, trastuzumab improves antitumor efficacy as measured by time to progression, response rate, and survival (abstract).
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960).
Moreover, it was known in the art that drug combinations produce higher rates of objective response and longer survival than single agents because it combines two anti-cancer agents, each operating via a different mechanism of action, and as such it could solve problems arising in the clinic, such as the development of resistance to drugs
15. Claims 13-31 and new claim 35 remain/are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-9 of US 10,940,181, in view of Clinical Trial Study NCT00349934 (version 1, first posted on 7/10/2006, IDS filed on 1/18/2023), and Hortobagyi (Semin Oncol, 2001, 28(suppl 18):43-47).
Claims 1-9 of US 10,940,181 disclose a method of treating or ameliorating a cancer in a human subject in need thereof, the method comprising administering to the subject an effective amount of: a LAG-3 protein, or a derivative of LAG-3 protein that is able to bind to MHC class II molecules, wherein the derivative of LAG-3 protein comprises recombinant soluble human LAG-3Ig fusion protein IMP321, wherein the LAG-3 protein or the derivative of LAG-3 protein binds to MHC class II molecules on APCs, thereby activating APCs and further activating T cells; and a programmed cell death protein-1 (PD-1) pathway inhibitor, wherein the PD-1 pathway inhibitor is selected from the group consisting of pembrolizumab and nivolumab; wherein the LAG-3 protein or the derivative of LAG-3 protein, and the PD-1 pathway inhibitor cause a synergistic activation of T cells in the subject, the synergistic activation of T cells in the subject being more than a sum of activation of T cells in the subject caused by administration to the subject of the LAG-3 protein or the derivative of LAG-3 protein alone and administration to the subject of the PD-1 pathway inhibitor alone,
wherein the LAG-3 protein, or derivative thereof, and the PD-1 pathway inhibitor are administered sequentially or co-administered to the subject, the LAG-3 protein, or derivative thereof, is administered after the PD-1 pathway inhibitor, the LAG-3 protein, or derivative thereof, is administered to the subject at a dose which is a molar equivalent of 0.25-30 mg of LAG-3Ig fusion protein IMP321, wherein a plurality of doses of the LAG-3 protein, or derivative thereof, is administered to the subject, the derivative of LAG-3 protein is the recombinant soluble human LAG-3Ig fusion protein IMP321, wherein the cancer is breast cancer.
The claims of the patent do not teach treating the patients with trastuzumab. However, these deficiencies are made up for in the teachings of NCT00349934 (version 1). and Hortobagyi
The teachings of NCT00349934 (version 1) and Hortobagyi have been set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have treated breast cancer with trastuzumab in view of Hortobagyi. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Hortobagyi teaches that as a single agent, trastuzumab has substantial and reproducible antitumor activity in HER2/neu-amplified metastatic breast cancer. In addition, when added to chemotherapy, trastuzumab improves antitumor efficacy as measured by time to progression, response rate, and survival (abstract).
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960).
Moreover, it was known in the art that drug combinations produce higher rates of objective response and longer survival than single agents because it combines two anti-cancer agents, each operating via a different mechanism of action, and as such it could solve problems arising in the clinic, such as the development of resistance to drugs
16. Claims 13-31 and new claim 35 remain/are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over
claims 1-40 of U.S. 10,736,940,
claims 16-17 of US 10,874,713,
claims 1-12 of US 12,214,012, and
claims 1-10 of US 11,684,654, in view of Clinical Trial Study NCT00349934 (version 1, first posted on 7/10/2006, IDS filed on 1/18/2023), and Hortobagyi (Semin Oncol, 2001, 28(suppl 18):43-47).
The rationales for the ejections are similar to those discussed above (see paragraphs 17-20).
Response to Applicant
In the response, applicant requested that the rejection be held in abeyance until the claims are held otherwise allowable. Since applicant did not specifically argue the rejections, all NSDP rejections are maintained for the reasons of record.
Conclusion
17. No claims are allowed.
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 o