DETAILED ACTION
Claims 1-20, submitted on March 24, 2023, are pending in the application and are rejected for the reasons set forth below. No claim is allowed.
This application, filed on or after March 16, 2013, is being examined under the first-to-file provisions of the Leahy-Smith America Invents Act (AIA ), Pub. L. No. 112-29, 125 Stat. 284 (2011). In the event that 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 statu-tory basis 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.
Claim Rejections – 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claims 1, 3-18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Fisher, PLoS One 2017;12(7):e0181654 in view of Ohmura, Anticancer Res. 2011 Jul.;31(7):2527-33 and Wang, J. Neurosurg. 2004;100(2):272-77.
Fisher (cited in applicant’s IDS1) discloses (see, e.g., the title of the document) therapy of malignant glioma, which is type of brain tumor, by administering 5-aminolevulinic acid (ALA) and hypothermia (p. 1), i.e., cooling, where the therapy is mediated by protoporphyrin IX (PpIX). The ALA was given by “IP injection” (see “In vitro PDT” at p. 6), i.e., intraperitoneal injection, although oral administration within the meaning of instant claims 9 and 18 would have been readily apparent to one of ordinary skill in the art. “[T]umors show a preferential uptake of ALA, increas-ing synthesis of PpIX” (p. 2) and selectivity for glioblastoma multiforme (GBM) is accomplished by “higher PpIX accumulation in the malignant tissue” (p. 15). The therapy further includes activation of the PpIX by irradiation with light (p. 6). The cooling resulted in “mild hypothermia” at a temperature of 32-34°C (p. 6). Although the experiments disclosed in Fisher were conducted on rodents, it is nevertheless implicit that the therapy would also be useful in treating humans; for example, the reference discloses that “hypothermic intervention could lead to considerable [human] patient outcome improvements” (p. 2) and the cancer cells discussed in the reference were of human origin (see “Cell culture” at p. 3).
The differences between the prior art and the claims at issue are that Fisher does not specifically disclose ultrasound as the activating step or inducing hypothermia by circulating a fluid around the patient.
Ohmura (also cited in applicant’s IDS), however, discloses (see, e.g., abstract) that focused ultrasound, i.e., treatment with a sonomechanical mechanism, was known in the prior art as a means of activating ALA when treating malignant glioblastoma.
Wang (also cited in the IDS) discloses (see Figs. 1-2 at p. 273 and the discussion thereof) a cooling helmet that pumps ice water, i.e., a cooling fluid, around the head of a patient in order to induce hypothermia of the brain.
It would have been prima facie obvious to one of skill in the art as of the effective filing date to use focused ultrasound as taught by Ohmura when practicing the treatment of Fisher. One would have been motivated to do so because ultrasound was known in the prior art as a means of activating ALA when treating malignant glioblastoma, and one would have had a reasonable expectation of success for the same reason. Furthermore, using ultrasound activation as taught by Ohmura instead of light activation as taught by Fisher would have been viewed as substituting one activation technique for another such technique and therefore prima facie obvious. See MPEP 2144.06(II), which discusses substituting equivalents known for the same purpose.
By adopting the cooling methods disclosed in Wang when practicing the glioblastoma therapy taught by Fisher/Ohmura one arrives at subject matter within the scope of the instant claims. Note that Fisher discloses the value and importance of hypothermia, but it does not provide any instructions about how it is accomplished in human patients. One therefore would have been motivated looked to the prior art for this missing information, and Wang suggests an answer to this question. One would have had a reasonable expectation of success because it would have been apparent that the apparatus of Wang would be useful in treating a cancer patient.
The present application appears to represent applicant’s discovery of a mechanism of action (see, e.g., instant claims 3-8, 13, and 15-17) whereby the therapy outlined above operates. The discovery, however, of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render it patentably new to the discoverer. The claiming of a new use, new function, or unknown property that is inherently present in the prior art, although not necessarily specifically disclosed therein, does not make the instant claims patentable. See MPEP 2112. Furthermore, mere recognition of such latent prop-erties in the prior art does not render nonobvious an otherwise known invention. Granting a patent on the discovery of an unknown but inherent function “would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art.” The fact that applicant has evidently recognized other advantages that would flow naturally from following the suggestion of the prior art as outlined above “cannot be the basis for patentability when the differences would otherwise be obvious.” See MPEP 2145(II). The cited references disclose using the same drug (5-aminolevulinic acid) for the same reason (treatment of glioblas-t-oma) in the same manner (activating protoporphyrin IX) as recited in the instant claims, so the examiner concludes that the mechanism of action recited in the claims would be inherent in a method of treating glioblastoma as taught by Fisher while adopting the cooling methods taught by Wang. Functional claim limitations relating to the PpIX producing reactive oxygen species and thereby causing apoptosis or necrosis of the tumor cells (claims 1 and 14), production of PpIX by a heme pathway (claims 3 and 15), selective accumulation of PpIX in tumor cells via reduced expression of ferrochelatase (claims 3 and 15), and accumulation in mitochondria of tumor cells (claim 4), the PpIX converting dissolved molecular oxygen into the reactive oxygen species (claim 8), causing thermal damage (claim 13), causing a mechanical phenomenon, such as cavitation (claims 7 and 17), and so forth have therefore not been accorded patentable weight. See MPEP 2173.05(g) and 2111.04(I).
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 possi-ble 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 provi-sions 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 accompa-nied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejec-tion 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 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 11,318,332 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. Claim 1 of the ‘332 Patent is directed to a non-invasive method of treating tumors with an oral pro drug, comprising: instructing oral admin-istration of a pro drug to a patient with tumor cells, wherein the pro drug comprises 5-aminolevulinic acid (5-ALA), wherein said 5-ALA results in increased production of protopor-phyrin IX, wherein said protoporphyrin IX is preferentially accumulated in said tumor cells, activating said protoporphyrin IX via defocused or planar ultrasound to produce a reactive oxygen species (ROS) thereby causing apoptosis of said tumor cells, wherein the activating of said proto-porphyrin IX comprises sonoluminescence; and cooling the patient by circulating a cooling fluid to a membrane configured for conforming to a skin surface of the patient.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 11,617,904 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. Claim 1 of the ‘904 Patent, of which the present application is a continuation, is directed to a non-invasive method of treating a tumor with a pro drug, comprising: administering a pro drug to a patient with tumor cells, wherein said pro drug comprises 5-aminolevulinic acid (5-ALA), wherein said 5-ALA results in increased production of protoporphyrin IX via a heme biosynthesis pathway, wherein said protoporphyrin IX is selectively accumulated in said tumor cells, activating said protoporphyrin IX via ultrasound, wherein said ultrasound is defocused or planar, wherein said activating said protoporphyrin IX results in said protoporphyrin IX becoming cytotoxic thereby causing apoptosis of said tumor cells; and cooling said patient by circulating a cooling fluid around said patient.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 11,724,132 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. Claim 1 (in part) of the ‘132 Patent is directed to a method of producing zero vergence ultrasound waves for sonodynamic therapy to treat tumor cells harboring a sonosensitizer, comprising: coupling a sonodynamic therapy device to a skin surface over a treatment region with the tumor cells of a patient, the sonodynamic therapy device comprising a controller, a flexible membrane coupled to a shell and a cooling system, wherein each of the piezoelectric ultrasound transducer elements is configured to emit a zero vergence ultrasound wave that delivers a planar ultrasound wave to the tumor cells, driving the array of piezoelectric ultrasound transducer elements with a signal to activate the sonosensitizer in the tumor cells of the patient, wherein the sonosensitizer comprises protoporphyrin IX, wherein the flexible membrane is configured for conforming to the patient at the skin surface; wherein the cooling system is configured to absorb heat through the skin surface over a treat-ment region. Dependent claim 12 further requires administering a pro drug to the patient, wherein the pro drug comprises 5-aminolevulinic acid (5-ALA), wherein the 5-ALA results in increased production of the protoporphyrin IX.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 11,865,372 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. Claim 1 of the ‘372 Patent is directed to a non-invasive method of treating cancer with a drug, comprising: administering a drug to a patient with cancerous cells, wherein said drug results in increased production of protoporphyrin IX, wherein said protoporphyrin IX is selectively accumulated in said cancerous cells, activating said protoporphyrin IX via ultrasound, wherein said ultrasound is defocused or planar, wherein said activating said protoporphyrin IX results in said protoporphyrin IX becoming cytotoxic thereby causing apoptosis of said cancer cells; and cooling said patient by circulating a cooling fluid.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 11,872,414 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. Claim 1 (in part) of the ‘414 Patent is drawn to a method of producing ultrasound waves for sonodynamic therapy to treat tumor cells harboring a sonosensitizer, comprising: coupling a sonodynamic therapy device to a skin surface over a treatment region with the tumor cells of a patient, the sonodynamic therapy device, comprising: a controller, a patient interface, and a cooling system, wherein the patient interface comprises an array of piezoelectric ultrasound transducer elements and at least one of a cap, a rigid shell and a flexible shell, wherein each of the piezoelectric ultrasound transducer elements comprises an emitting surface configured to emit ultrasound waves, wherein the ultrasound waves are planar or defocused, driving the array of piezoelectric ultrasound transducer elements with a signal to activate the sonosensitizer in the tumor cells of the patient, wherein the sonosensitizer comprises a porphyrin compound, wherein the sonodynamic therapy device is configured to acoustically couple the array of piezoelectric ultrasound transducer elements to the skin surface, circulating a fluid in the cooling system, wherein the cooling system is configured to absorb heat through the skin surface over the treatment region. Dependent claim 11 further requires “administering a pro drug to the patient, wherein the pro drug comprises aminolevulinic acid (ALA), wherein the ALA results in increased production of the porphyrin compound.”
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 11,980,777 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. Claim 10 (in part) of the ‘777 Patent is directed to a method of producing randomized ultrasound waves for sonodynamic therapy to treat tumor cells harboring a sonosensitizer, comprising: administering aminolevulinic acid (ALA) to a patient, wherein the ALA results in increased production of a sonosensitizer, coupling a sonodynamic therapy device to a skin surface over a treatment region with the tumor cells of the patient, wherein the sonodynamic therapy device comprises: an array of piezoelectric ultrasound trans-ducer elements, wherein each of the piezoelectric ultrasound transducer elements comprises an emitting surface configured to emit randomized ultrasound waves, wherein the randomized ultrasound waves are planar or defocused, wherein the sonodynamic therapy device is config-ured to acoustically couple the array of piezoelectric ultrasound transducer elements to the skin surface, wherein the patient interface is configured for non-invasively conforming to the patient at the skin surface. Dependent claim 11 further requires circulating a fluid in a cooling system to absorb heat through the skin surface over the treatment region.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 12,097,392 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. Claim 1 (in part) of the ‘392 Patent is directed to a 1. An ultrasound transducer system that generates an incoherent acoustic pressure field for activating a sonosensitizer in conjunction with providing sonodynamic therapy, the ultrasound transducer system comprising: an ultrasound transducer array comprising a plurality of ultrasonic piezoelectric transducer elements, wherein the plurality of ultrasonic piezoelectric transducer elements is configured to generate the incoherent acoustic pressure field via an aperture sized and configured with an energy profile to saturate a treatment volume to ensure treatment of a targeted lesion of cancer cells and extraneous cancer cells located within a tissue of a patient by activating the sonosensitizer located within the tissue of the patient, wherein each ultrasonic piezoelectric transducer element in the plurality of ultrasonic piezoelectric transducer elements comprises an emitting surface configured to emit planar acoustic waves or defocused acoustic waves, wherein the signal is configured to minimize a spatial variation of an acoustic wave inten-sity to activate the sonosensitizer at the targeted lesion of cancer cells with the planar acoustic waves or the defocused acoustic waves, and wherein the signal is configured with a duty cycle to drive each ultrasonic piezoelectric transducer element in the plurality of ultrasonic piezoelectric transducer elements to generate (i) a high temporal peak acoustic intensity sufficient to activate the sonosensitizer at the targeted lesion of cancer cells with the planar acoustic waves or the defocused acoustic waves and (ii) a low temporal average acoustic intensity to preserve tissue. Dependent claim 4 further requires a cooling system configured to remove excess heat from the patient, wherein the cooling system comprises a flexible cavity configured for circulation of a cooling fluid. Dependent claim 6 requires that the sonosensitizer is aminolevulinic acid (ALA), among other things.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 12,138,488 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. Claim 1 of the ‘488 Patent is drawn to a non-invasive method of treating cancer with a drug, comprising: administering a drug to a patient with cancer cells, wherein said drug results in increased production of a porphyrin compound, wherein said porphyrin compound is accumulated in said cancer cells, activating said porphyrin compound via ultrasound, wherein said ultrasound is defocused or planar, wherein said activat-ing said porphyrin compound results in said porphyrin compound causing apoptosis of said cancer cells; and cooling said patient by circulating a cooling fluid. Dependent claim 8 further comprises oral administration of aminolevulinic acid (ALA).
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 18/919,841 (reference application) in view of Ohmura and Wang as applied above. Although the claims at issue are not identical, they are not patentably distinct from each other. See the claims submitted on January 8, 2025 in the ‘841 Application. Briefly, these claims are directed to a method of treating cancer comprising administering ALA (see claim 8) together with defocused or planar ultrasound (claim 4). Although the claims of the ‘841 Application do not specifically require cooling the patient, it nevertheless would have been prima facie obvious for substantially the same reasons discussed above. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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THEODORE R. HOWELL
Primary Examiner
Art Unit 1628
/THEODORE R. HOWELL/Primary Examiner, Art Unit 1628
December 3, 2025 (revised December 17, 2025)
1 See the information disclosure statement (IDS) submitted on March 4, 2023. Courtesy copies of Fisher, Ohmura, and Wang are included herewith.