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 amended claims of 01/19/2024. Claims 1, 7, 9, 11, 13, 15-18, 25-26, 30, 32, 39, and 42-47 are pending. Claims 1, 7, 9, 11, 13, 15-18, 25-26, 30, 32, 39, and 42-47 are examined.
Election/Restrictions
Applicant’s election without traverse of bosentan, breast cancer, nivolumab, PD-1, collagen, bosentan, and nivolumab in the reply filed on 05/26/2026 is acknowledged.
A search for the elected species retrieved prior art, thus, the search will not be unnecessarily extended to further species in this action, per Markush search practice. The elected species read on all pending claims.
Note, during the search for the elected species, Examiner found art pertaining to another species of “agent that decompresses blood vessels”: metformin and species of “chemotherapeutic”: gefitinib. This art is also applied below.
Priority
The effective filing date is 12/11/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/26/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 44 and 47 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (abstract idea – mental processes) without significantly more. The claims recite: methods for determining the effective amount of an agent AND predicting the response to treatment, respectively, comprising measuring physical properties of a tumor. Determining, measuring, and predicting are mental process judicial exceptions. These judicial exceptions are not integrated into a practical application because the steps recited do not affect a particular treatment or prophylaxis of a disease and, at most, amount to insignificant extra solution activity and suggestions to “apply it”. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the elements are mere suggestions to “apply it” and are well-understood, routine, and conventional activity.
Step 1: Is the claim drawn to a process, machine, manufacture, or composition of matter?
Yes, the broadest reasonable interpretation (BRI) of the claims as a whole are drawn to processes of measuring physical properties of solid tumors before and after administration of an agent that decompresses blood vessels.
Revised Step 2A:
Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes, the BRI of claim 44 is drawn to an abstract idea “determining an effective amount of an agent” and “measuring the blood flow and/or stiffness of the solid tumor” which are mental processes – i.e., concepts performed in the human mind including an observation, evaluation, etc. Similarly, the BRI of claim 47 is drawn to an abstract idea “predicting response to treatment” and “measuring the blood flow and/or stiffness of the solid tumor” which are mental processes of the same variety.
Prong Two: Does the Claim Recite Additional Elements that Integrate the Judicial Exception (JE) into a Practical Application?
No.
Regarding claim 44: Determination of an effective amount of an agent that decompresses blood vessels by measuring the blood flow/stiffness of a tumor is not directed to any particular treatment and/or prophylaxis of a disease. While “measuring” is a mental process JE, if considered as an additional element to the JE “determining”, measurement of physical properties of the tumor is insignificant extra-solution activity, e.g., mere data gathering (see MPEP 2106.05.I.A.). Further, the step of “administering” an effective amount of “an agent that decompresses blood vessels” is recited at a high level of generality that it is, at best, mere instructions to apply the exception of “determining” an effective amount. Further, the administration does not cause any particular treatment or prophylaxis, since the administration of the “agent” is necessary within the claimed method to even perform the determination. As such, it may also be considered part of the insignificant extra-solution activity, i.e., just a step towards data gathering (measuring and determining).
Regarding claim 47: Prediction of a response to a chemotherapeutic agent by measuring the blood flow/stiffness of a tumor is not directed to any particular treatment and/or prophylaxis of a disease. The limitations “measuring” and “administering” are analyzed with the same logic applied to claim 44, above.
For both claims, the “agent that decompresses blood vessels” could also refer to a “field of use”. See also MPEP 2106.04(d)(2) regarding a discussion of why a “field of use” limitation fails to integrate a judicial exception into a practical application of that exception.
Step 2B: Does the claim recite additional elements that amount to significantly more than the JE?
No. The additional elements to the JEs of both claims 44 and 47 are the “measuring” of the blood flow and/or stiffness of the tumor and the “administration” of the “agent”. It is well-understood, routine, and conventional (WURC) in the art to measure blood flow and/or stiffness of a tumor. STYLIANOPOULOS (Stylianopoulos, T. et al., PNAS, 2012, 109(38), 15101-15108; cited IDS of 05/26/2026) discloses lymphatic and blood vessels in tumors are compressed by solid stress, techniques to measure such solid stress, and depletion of such stress decompresses blood vessels (Pg. 15101 Abstract). Thus, the art establishes it is WURC to measure/track such physical properties of tumors. Further, the administration of the “agent” to decompress blood vessels is also WURC. STYLIANOPOULOS discloses administration of sonic hedgehog pathway inhibitors decompresses the blood vessels and reduces stress (Pg. 15101 Abstract). Moreover, as stated above, the “administration” is a suggestion to apply the JEs and insignificant extra-solution activity to achieve the JEs.
Thus, claims 44 and 47 are not eligible subject matter under 35 USC 101.
Claims 45-46 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (abstract idea – mental processes) without significantly more. The claims recite: methods for treating a solid tumor comprising measuring physical properties of the tumor (claim 45-46) and determining responsiveness to a chemotherapeutic agent based on the measured physical properties (claim 46). Measuring and determining are mental process judicial exceptions. The judicial exceptions are not integrated into a practical application because the steps recited do not affect a particular treatment or prophylaxis of a disease and, at most, amount to insignificant extra solution activity and suggestions to “apply it”. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions because the elements are mere suggestions to “apply it” and are well-understood, routine, and conventional activity.
Step 1: Is the claim drawn to a process, machine, manufacture, or composition of matter?
Yes, the broadest reasonable interpretation (BRI) of the claims as a whole are drawn to processes of measuring physical properties of solid tumors before and after administration of an agent that decompresses blood vessels and further administration of a generic chemotherapeutic agent.
Revised Step 2A:
Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes, the BRI of claim 45 is drawn to an abstract idea “measuring the blood flow and/or stiffness of the solid tumor” which is a mental process – i.e., concept performed in the human mind including an observation, evaluation, etc. Similarly, the BRI of claim 46 is drawn to an abstract idea “measuring the blood flow and/or stiffness of the solid tumor” and “determining that the subject is responsive” which are both mental processes of the same variety (observing, evaluating).
Prong Two: Does the Claim Recite Additional Elements that Integrate the Judicial Exception (JE) into a Practical Application?
No.
Regarding claim 45: The steps (a) and (c) comprising “measuring” are mental process JEs. The step (b) of “administering” an effective amount of “an agent that decompresses blood vessels” is recited at a high level of generality that it is at best mere instructions to apply the exception of “measuring” a change in blood flow/tumor stiffness. To measure such change, the practitioner would have to effect blood flow/stiffness in some way and the instant claim is very generic as to how such change is created (e.g., no mechanism of action or compound class is recited). Further, the administration does not cause any particular treatment or prophylaxis, since the administration of the “agent” does not actually treat the solid tumor. As such, it may also be considered insignificant extra-solution activity, i.e., just a step towards data gathering (measuring). The step (d) of “administering” the chemotherapeutic agent is also recited at such a generic level, and is not specified as an effective amount. At best, step (d) is mere instructions to apply the exception; i.e., apply the measured change in tumor properties to a field of use which is generic chemotherapy/tumor treatment. See MPEP 2106.05(f): “claim limitations that attempt to cover any solution to an identified problem” (e.g., generic chemotherapeutic agent) with “no description of the mechanism for accomplishing the result” do not integrate the JE into a practical application.
Regarding claim 46: steps (a)-(c) and (e) are analyzed with the same logic applied to claim 45, above. Since step (d) is the “determining” JE, it is not considered an additional element. If step (d) is considered as an additional element to the “measuring” JE, determination of a subject’s response to a chemotherapeutic agent does not take any steps towards a particular treatment/prophylaxis. Even when combined with step (e), the determination and administration of a generic chemotherapeutic is still, at most, a suggestion to apply the JE.
For both claims, the “agent that decompresses blood vessels” could also refer to a “field of use”. See also MPEP 2106.04(d)(2) regarding a discussion of why a ‘field of use’ limitation fails to integrate a judicial exception into a practical application of that exception.
Step 2B: Does the claim recite additional elements that amount to significantly more than the JE?
No. The additional elements to the JEs of both claims 45 and 46 are the “administration” of the “agent that decompresses both vessels” and the “chemotherapeutic agent”. It is well-understood, routine, and conventional (WURC) in the art to administer both types of agents to tumors. STYLIANOPOULOS (Stylianopoulos, T. et al., PNAS, 2012, 109(38), 15101-15108; cited IDS of 05/26/2026) discloses administration of agents to decompress tumor blood vessels and increase tumor perfusion for improved efficacy of administered chemotherapies (Pg. 15101 Abstract). Moreover, as stated above, the “administration” of either agent is a suggestion to apply the JEs and insignificant extra-solution activity to achieve the JEs.
Thus, claims 45-46 are not eligible subject matter under 35 USC 101.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 45 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 45 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: if the blood flow of the solid tumor is not increased or if the stiffness of the solid tumor is not decreased, is the chemotherapeutic agent administered? Claim 45 is a conditional claim with contingent limitations (see MPEP 2111.04(II)) because the word “if” precedes a condition under which the chemotherapeutic agent is administered. There are two embodiments of claim 45: 1) blood flow increased/stiffness decreased, so the chemotherapeutic is administered or 2) blood flow decreased/stayed the same and/or stiffness increased/stayed the same. Embodiment 2 does not involve any steps. Thus, the method of embodiment 2 is incomplete. Thus, the metes and bounds of the claim are undefined rendering the claim indefinite.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 44-47 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by PULIDO (Pulido, I. et al., Cancer Research, 1 Oct. 2020, 80(19), 4224-4232; cited IDS of 05/26/2026).
PULIDO teaches administration of bosentan to a tumor increases the blood flow in the tumor (Pg. 4229 Fig. 4A); i.e., blood flow was measured before and after administration of an agent that decompresses blood vessels (bosentan) and an effective amount of the agent was determined. PULIDO further teaches the increase in blood flow improved drug delivery to the tumor (Pg. 4229 Fig. 4) wherein in vivo administration of the chemotherapeutic gefitinib and bosentan resulted in smaller tumor volume compared to gefitinib alone (Pg. 4229 Fig. 4C & Pg. 4230 Left col. ¶1); i.e., the subject was determined/predicted to be responsive to a chemotherapeutic agent since the blood flow increased in the tumor and the subject was administered the chemotherapeutic agent (gefitinib).
Claims 44-47 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by FUKUMURA (US 2018/0064662; cited IDS of 05/26/2026).
FUKUMURA teaches methods for improving delivery/efficacy of a chemotherapy by administering metformin to reduce the amount of extracellular matrix collagen-I and hyaluronan in a tumor in a subject which allows for blood vessel decompression and reperfusion (Pg. 1 ¶5 & Pg. 22-23 ¶268-286). In mouse models, metformin significantly reduced the density of collagen-I and hyaluron activated cells in tumors by 54% and 57%, respectively, showing that metformin reduced desmoplasia in tumors (Pg. 55 ¶702). Desmoplasia refers to fibro-inflammatory tumor microenvironment and reduced perfusion (Pg. 1 ¶5-6). FUKUMURA teaches a method of improving the delivery/efficacy of a cancer therapy in a subject comprising administering the metformin and an immune checkpoint inhibitor (Pg. 79 claim 2) wherein the subject has a solid tumor (Pg. 79 claim 41). Exemplary immune checkpoint inhibitors include nivolumab (Pg. 6 ¶86).
Regarding instant claims 44 and 47, the tumor stiffness/blood flow is measured via collagen-I & hyaluron both before and after administration of metformin. Note, the instant specification recites species of the instant “agent” including metformin (Pg. 38-39 ¶120). Since metformin is shown to decrease stiffness/increase blood flow, the method taught by FUKUMURA inherently determines an effective amount of metformin (instant 44). Further, since the delivery/efficacy of a chemotherapeutic is increased by metformin administration the subject has been predicted to respond to treatment with the chemotherapeutic agent (instant 47).
Regarding instant claims 45-46, the steps (a)-(c) and any determination of change in stiffness/blood flow are anticipated as explained for claims 44 & 47, above. For claim 46, step (d) determining the subject is responsive to a chemotherapeutic agent is met in the same way the prediction of claim 47 is met, above. For step (d) of claim 45 and step (e) of claim 46, the administration of the chemotherapeutic agent is met by the teaching of Pg. 1 ¶5 & Pg. 79 claim 2; further the agent is nivolumab (Pg. 6 ¶86).
Claim Rejections - 35 USC § 103
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, 7, 11, 13, 15-18, 30, 32, 39, and 42-47 are rejected under 35 U.S.C. 103 as being unpatentable over:
PULIDO (Pulido, I. et al., Cancer Research, 1 Oct. 2020, 80(19), 4224-4232 + supplemental information p.1-5; cited IDS of 05/26/2026 without SI, a copy is attached to provide SI)
in view of:
CINAR (Cinar, I. et al., The Eurasian Journal of Medicine, 28 Oct. 2020, 52(3), 277-282; cited IDS of 05/26/2026),
STYLIANOPOULOS (Stylianopoulos, T. et al., PNAS, 2012, 109(38), 15101-15108; cited IDS of 05/26/2026),
KRUGER (Kruger, M. et al., Journal of Clinical Medicine, 18 March 2020, 9, 1-29), and
ZOU (Zou, Y. et al., Therapeutic Advances in Medical Oncology, 17 Aug. 2020, 12, 1-7).
The instant claims are drawn to: treatment of a breast cancer tumor via administration of bosentan and nivolumab to a human subject to reduce tumor stiffness and collagen I levels; and a kit comprising bosentan and nivolumab.
Determining the Scope and Contents of the Prior Art:
PULIDO teaches tumor cells secrete endothelin-1, a vasoconstrictor, limiting the blood flow carrying drugs to the tumor (Pg. 4230 Discussion ¶1-2). Administration of bosentan increases tumor blood flow improving drug delivery to the tumor (Pg. 4229 Fig. 4). Administration of a chemotherapeutic, gefitinib, and bosentan to mice resulted in smaller tumor volume compared to gefitinib alone (Pg. 4229 Fig. 4C & Pg. 4230 Left col. ¶1). Bosentan is an endothelin receptor inhibitor (Pg. 4224 Abstract). A combination of bosentan and gefitinib are administered daily (Supplemental Info Pg. 4 ¶4).
CINAR teaches breast cancer is the most common type of cancer and a significant cause of death in women (Pg. 277 Intro ¶1). Endothelin-1, produced by breast epithelial cells (Pg. 277 Intro ¶1), plays a critical role in breast cancer progression (Pg. 277 Abstract). Bosentan is selective for endothelin-1 (Pg. 281 Col. 2 ¶1) and exerts anti-proliferative and anti-migratory effects on breast cancer by inhibiting endothelin-1 (Pg. 281 Col. 3 ¶2).
STYLIANOPOULOS teaches growth-induced solid stress in tumors reduces blood flow leading to hypoxia, tumor progression, and reduced efficacy of chemo- and immunotherapies (Pg. 15101 Abstract). Components of the extracellular matrix (ECM), collagen and hyaluronan, contribute to growth-induced solid stress (Pg. 15104 Col. 2 ¶2 – Pg. 15105 Col. 1 ¶2). Decreasing levels of ECM collagen and hyaluronan decreases the solid stress in breast cancer tumors (Pg. 15104 Fig. 3D&F).
KRUGER teaches endothelin-1 increases the ECM production of collagen I and inhibits collagenase; bosentan inhibits endothelin-1 induced ECM deposition (Pg. 15 Sect. 7.).
ZOU teaches, in clinical trials, breast cancer has modest response to immune checkpoint inhibitors (ICI) (Pg. 1 Abstract). The anti-PD-1 ICI nivolumab has a positive overall response rate (ORR); further, anti-CTLA-4 ICI when used with another ICI has a positive ORR (Pg. 5-7 Table 1). ZOU teaches greater ICI efficacy corresponds to greater T cell infiltration level (Pg. 2 Col. 1 ¶2).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
PULIDO does not teach breast cancer or administering an ICI. CINAR does not teach administering an ICI. STYLIANOPOULOS and KRUGER do not teach the combination of bosentan and ICI. ZOU does not teach administering bosentan.
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 of treating breast cancer and possesses the technical knowledge necessary to make adjustments to the treatment to optimize/enhance the reduction of ECM stress and increase in blood flow. Said artisan has also reviewed the problems in the art regarding tumor ECM stress/blood flow 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 PULIDO in view of: CINAR, STYLIANOPOULOS, KRUGER, and ZOU.
Regarding claims 1, 13, 15-16, 39, and 42, the artisan would find it obvious to treat breast cancer with a combination of bosentan and an ICI (nivolumab, anti-PD-1). The artisan would have motivation to administer bosentan since bosentan increases tumor blood flow, drug delivery, and chemotherapy efficacy in vivo, as recognized by PULIDO (Pg. 4229 Fig. 4). The artisan would have an expectation of success since bosentan reduces proliferation and migration of breast cancer, as recognized by CINAR (Pg. 281 Col. 3 ¶2).
It would be obvious to substitute the gefitinib of PULIDO with the nivolumab of ZOU since the two are functional equivalents (i.e., cancer treatments). Further, the artisan would have an expectation of success administering nivolumab since it is effective in breast cancer clinical trials, as recognized by ZOU (Pg. 5-7 Table 1). Moreover, the artisan would have a reasonable expectation of success that by combining bosentan and nivolumab, one would have a composition useful for treating breast cancer since both are taught by the prior art as suitable for such treatment. As set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980), it is prima facie obvious to combine two agents which are each taught by the prior art to be useful for the same purpose. The idea of combining them flows logically from having been individually taught in the prior art.
The artisan would be motivated to treat a human subject since bosentan is shown to be effective in vivo (PULIDO Pg. 4229 Fig. 4), nivolumab is effective in human clinical trials (ZOU Pg. 5-7 Table 1), and breast cancer is prevalent in women (CINAR Pg. 277 Intro ¶1).
Regarding claims 7 and 11, Since bosentan increases blood flow to tumors (PULIDO Pg. 4229 Fig. 4) via inhibiting endothelin-1 (PULIDO Pg. 4230 Discussion ¶1-2), and since bosentan inhibits endothelin-1 deposition of ECM collagen-I (KRUGER Pg. 15 Sect. 7.), and since collagen-based ECM stress/stiffness in tumors reduces blood flow leading to hypoxia, the artisan would expect bosentan to reduce collagen-I in the ECM leading to reduced stiffness, improved blood flow, and reduced hypoxia.
Further, since ICIs can increase T cell infiltration (ZOU Pg. 2 Col. 1 ¶2), by increasing blood flow and drug delivery to the tumor, the artisan would expect the bosentan to also allow higher levels of T cells to infiltrate/colocalize with the tumor.
The artisan would expect this to be effective in breast cancer since endothelin-1 plays a critical role in breast cancer, recognized by CINAR (Pg. 277 Abstract & Intro ¶1).
Regarding claim 17, the artisan would have a reasonable expectation of success in combining nivolumab with an anti-CTLA-4 ICI since anti-CTLA-4 is effective in breast cancer when combined with another ICI (ZOU Pg. 5-7 Table 1). Further, as set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980), it is obvious to combine two agents (nivolumab & CTLA-4 ICI) taught by the prior art as useful for the same purpose (cancer treatment). The idea of combining them flows logically from having been individually taught in the prior art.
Regarding claims 18, 30, and 32, the artisan would be motivated to administer the bosentan at least once a day, for at least a portion of the time that the ICI is administered, since PULIDO teaches daily administration of combined bosentan and chemotherapeutic (SI Pg. 4 ¶4) results in smaller tumor volume compared to the chemotherapeutic alone (Pg. 4229 Fig. 4C & Pg. 4230 Left col. ¶1). The artisan would have a greater expectation of success in administering the two drugs in an overlapping timeframe. Smaller tumor volume would be an expected therapeutic effect of bosentan and a chemotherapeutic (ICI nivolumab). Additional improved therapeutic effects of bosentan are increased blood flow, reduced hypoxia, reduced collagen-I, and anti-proliferative/migratory effect, as discussed above.
Regarding claim 43, by virtue of the method of use being obvious, a kit comprising the two drugs, bosentan and nivolumab, would be obvious to the artisan in order to use the two drugs together. The teachings above could serve as instructions to use the two drugs. Further, see MPEP 2112.01, instructions for use are nonfunctional printed matter which do not distinguish the claimed product from the prior art.
Regarding claims 44-47, the combined references teach administration of bosentan and nivolumab for treatment of breast cancer (above) and PULIDO teaches the methods of claims 44-47 for bosentan and gefitinib (as explained in ¶16, above). Since nivolumab is replacing gefitinib as a functional equivalent (see claim 1 above), the artisan would find the instant methods obvious for the combination of bosentan and nivolumab.
Claims 1, 7, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over:
PULIDO (Pulido, I. et al., Cancer Research, 1 Oct. 2020, 80(19), 4224-4232 + supplemental information p.1-5; cited IDS of 05/26/2026 without SI, a copy is attached to provide SI)
in view of:
CINAR (Cinar, I. et al., The Eurasian Journal of Medicine, 28 Oct. 2020, 52(3), 277-282; cited IDS of 05/26/2026),
STYLIANOPOULOS (Stylianopoulos, T. et al., PNAS, 2012, 109(38), 15101-15108; cited IDS of 05/26/2026),
KRUGER (Kruger, M. et al., Journal of Clinical Medicine, 18 March 2020, 9, 1-29),
ZOU (Zou, Y. et al., Therapeutic Advances in Medical Oncology, 17 Aug. 2020, 12, 1-7),
as applied to claims 1 and 7 above, and further in view of:
SIGRIST (Sigrist, R.M.S. et al., Theranostics, 2017, 7(5), 1303-1329).
The instant claims are drawn to treatment of a tumor via administration of bosentan and nivolumab, wherein the tumor stiffness is reduced and is measured via ultrasound elastography.
Determining the Scope and Contents of the Prior Art:
The combination of PULIDO in view of: CINAR, STYLIANOPOULOS, KRUGER, and ZOU teaches the method of claims 1 and 7, above.
SIGRIST teaches ultrasound elastography (USE) is an imaging technique capable of quantitative assessments of tissue stiffness, with use in clinical routine for characterization of breast lesions (Pg. 1303 Introduction). USE has the highest specificity and sensitivity compared to other modalities used to characterize breast lesions (Pg. 1315 Col. 2 ¶3).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
PULIDO, CINAR, STYLIANOPOULOS, KRUGER, and ZOU do not teach measurement with USE.
SIGRIST does not teach the instant treatment.
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 methods useful for treating a tumor and possesses the technical knowledge necessary to make adjustments to the methods used to characterize the tumor to optimize/enhance the treatment outcome. Said artisan has also reviewed the problems in the art regarding tissue stiffness imaging 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 PULIDO in view of: CINAR, STYLIANOPOULOS, KRUGER, and ZOU, further in view of SIGRIST.
PULIDO in view of: CINAR, STYLIANOPOULOS, KRUGER, and ZOU teach the method of claims 1 and 7 wherein bosentan reduces tumor tissue stiffness. The artisan would be motivated to utilize USE to measure the tissue stiffness since USE provides quantitative measurements, is routinely used in clinical evaluation of breast lesions (e.g., malignant tumor), and has high specificity and sensitivity, as recognized by SIGRIST.
Claims 1 and 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over:
PULIDO (Pulido, I. et al., Cancer Research, 1 Oct. 2020, 80(19), 4224-4232 + supplemental information p.1-5; cited IDS of 05/26/2026 without SI, a copy is attached to provide SI)
in view of:
CINAR (Cinar, I. et al., The Eurasian Journal of Medicine, 28 Oct. 2020, 52(3), 277-282; cited IDS of 05/26/2026),
STYLIANOPOULOS (Stylianopoulos, T. et al., PNAS, 2012, 109(38), 15101-15108; cited IDS of 05/26/2026),
KRUGER (Kruger, M. et al., Journal of Clinical Medicine, 18 March 2020, 9, 1-29), and
ZOU (Zou, Y. et al., Therapeutic Advances in Medical Oncology, 17 Aug. 2020, 12, 1-7)
as applied to claim 1 and further in view of:
ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53).
The instant claims are drawn to administration of bosentan before administration of the checkpoint inhibitor.
Determining the Scope and Contents of the Prior Art:
The combination of PULIDO in view of: CINAR, STYLIANOPOULOS, KRUGER, and ZOU teaches the method of claim 1, above. PULIDO teaches daily administration of bosentan in combination with the chemotherapeutic (SI Pg. 4 ¶4).
ANSEL teaches the schedule of dosage or the dosage regimen is determined based on a drug’s duration of action, pharmacokinetics, and characteristics of the dosage form (Pg. 40 Right Col. para 2) and the effective dosing may be different for different patients (Pg. 48 Left Col. para 4).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
PULIDO, CINAR, STYLIANOPOULOS, KRUGER, and ZOU do not teach administration of bosentan before the ICI.
ANSEL does not teach administration of bosentan and an ICI.
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 treating cancer and possesses the technical knowledge necessary to make adjustments to the administration regimen to optimize/enhance treatment outcomes. Said artisan has also reviewed the problems in the art regarding treatment regimens 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 PULIDO in view of: CINAR, STYLIANOPOULOS, KRUGER, and ZOU, further in view of ANSEL.
The artisan would be motivated to optimize the dosing/treatment regimen of bosentan in relation to the ICI administration.
MPEP 2144.05(II)(A) provides guidance about the routine optimization of prior art conditions: "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).”
MPEP 2144.05(I) provides guidance about overlapping ranges: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists…Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.”
Here, PULIDO teaches combination administration of bosentan and the chemotherapeutic (SI Pg. 4 ¶2), this approaches the instant administration of bosentan prior to the ICI (i.e., chemotherapeutic). Since dosing and dosage regimens may be modified based on drug and patient parameters, as recognized by ANSEL, the artisan would recognize the dosage timings/regimen of bosentan as a result-effective variable, i.e., a variable that achieves a recognized result. Thus, the dosage regimen is analogous to the “concentration” recited in the MPEP and may be optimized by routine experimentation. Absent any evidence demonstrating the contrary, the determination of the optimum or workable dosing of bosentan would have been well within the practice of the artisan given the guidance of the prior art.
Moreover, since PULIDO teaches bosentan increases blood flow to improve drug delivery to the tumor (Pg. 4229 Fig. 4), the artisan would recognize the timing of bosentan administration as a variable affecting delivery of the chemotherapeutic (i.e., ICI) to the tumor. The artisan would be motivated to optimize the timing of bosentan administration, based on pharmacokinetics and tumor characteristics, in order to properly prepare the tumor for the delivery of the ICI (e.g., nivolumab) as to optimize the increase in delivery/efficacy thereof. Via routine experimentation the determination of bosentan administration at least 1 day, 2 days, 3 days, or 5 days prior to the ICI/nivolumab would have been well within the practice of the artisan.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 44-47 are provisionally rejected on the ground of anticipatory nonstatutory double patenting as being unpatentable over claim 48 of copending Application No. 18/717,876 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Reference claim 48 is drawn to a method for treating a solid tumor in a subject comprising: (a) measuring the blood flow and/or stiffness of the solid tumor, (b) administering to the subject an effective amount of ketotifen, (c) measuring the blood flow and/or stiffness of the tumor after administering ketotifen, (d) determining the subject is responsive to a chemotherapeutic agent based on the increase in blood flow or decrease in stiffness, and (e) administering the chemotherapeutic agent to the subject determined to be responsive. Ketotifen is a species of the instant “agent that decompresses blood vessels” based on the reference claim steps. Note, the instant specification recites species of the instant “agent” including ketotifen (Pg. 38-39 ¶120).
The reference claim anticipates the method of instant claim 44 since reference steps (a)-(c) overlap with the instant steps and would necessarily comprise determination of the effective amount of ketotifen. Similarly, instant claim 47 is anticipated since reference steps (a)-(c) overlap with the instant steps and reference step (d) necessarily “predicts” the subject’s/tumor’s response to the chemotherapeutic agent.
The reference claim anticipates the methods of instant claims 45-46 since both instant and reference are directed to treating a solid tumor with ketotifen. Further, the reference steps (a)-(c) and (e) overlap with the steps of claim 45 and the reference steps (a)-(e) overlap with the steps of claim 46.
Since the steps of the reference claim overlap with the steps of the instant claims and the reference claim utilizes a species of the instant “agent”, the reference claims anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1, 7, 9, 11, 13, 15-18, 25-26, 30, 32, 39, and 42-47 are rejected.
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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