DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s reply filed on 8/24/2026 is acknowledged. Claims 1, 4-5, 7-8 and 12 are pending. Claims 2-3, 6 and 9-11 are canceled. Claim 12 is withdrawn. Claims 1, 4 and 7 have been amended.
3. Claims 1, 4-5 and 7-8 are under examination.
Objections Withdrawn
4. The objection to the abstract for using legal phraseology is withdrawn in view of applicant’s amendments.
5. The objection to claim 4 for reciting “antibody fragment” is withdrawn in view of applicant’s amendments.
Rejections Maintained
Claim Rejections - 35 USC § 103
6. 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.
7. Claims 1, 4-5 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Yip et al. (Molecular Pharmaceutics, 4(2): 241-251, 2007, IDS filed on 2/3/2023), in view of Baskaran et al. (Biomaterials Res. 22(25), pages 1-8, 2018) and Lustig et al. (Cancer, 98(8): 1767-1771, 2003).
Regarding claim 1, Yip teaches a method for killing tumor cells by targeting EGFR expressing cancer cells (tumor cells) with immunotoxin cetuximab-saporin (a conjugate of cetuximab that binds to EGFR on the surface of tumor cells) in combination with photochemical internalization (PCI), which used a photosensitizer TPPS2a (abstract). Yip teaches that PCI is based on the principles of photodynamic therapy (PDT), which is approved worldwide for different cancer indications (page 244, column 1, para 3).
Regarding claim 4, Yip teaches immunotoxin cetuximab-saporin. Cetuximab is an anti-EGFR antibody (abstract).
Regarding claim 5, Yip teaches immunotoxin cetuximab-saporin (abstract). Saporin is a cytotoxin.
Regarding claim 7, Yip teaches targeting EGFR expressing cancer cells (abstract).
Regarding claim 8, Yip teaches that colorectal cancer cells and head and neck cancer cells are EGFR expressing cancer cells (page 242, column 2, and 247, para 1).
Yip does not teach a medicament for treating EGFR expressing cancer comprising cetuximab-saporin, and talaporfin sodium or porfimer sodium.
Baskaran discloses that PDT induces tumor regressions and second generation photosensitizers such as Photofrin[Symbol font/0xE2] (Porfimer sodium) and Laserphyrin[Symbol font/0xE2] (Talaporfin) have been approved clinically (abstract and page 6, under subtitle Laserphyrin[Symbol font/0xE2]). Baskaran discloses that Talaporfin was approved in Japan in 2004 as a PDT for lung cancer, and was also employed for early head and neck cancer patients (page 6, under subtitle Laserphyrin[Symbol font/0xE2]). Baskaran discloses that Talaporfin PDT achieved better therapeutic response rate about 80% in over the year (page 6, under subtitle Laserphyrin[Symbol font/0xE2]). Talaporfin is going through the phase II trial for the treatment of colorectal neoplasms and liver metastasis (page 6, under subtitle Laserphyrin[Symbol font/0xE2]).
Lustig teaches phase I study of intertumoral photoactivation of talaporfin sodium with refractory solid tumors (abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of instant invention to have made a medicament comprising cetuximab-saporin, and talaporfin sodium or porfimer sodium for treating cancer in view of Yip, Baskaran and Lustig. One skilled in the art would have been motivated to do so because Yip teaches cetuximab-saporin can be combined with PDT or PCI for treating cancer, and Baskaran teaches that talaporfin and porfimer sodium are both second generation photosensitizers and have been approved clinically in treating various cancers.
"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).
In the instant case, both cetuximab-saporin and talaporfin sodium or porfimer sodium were used in the art to treat cancer. 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, and a change in the antigenicity of the tumor cells that would render them unreactive with one antibody. One of ordinary skill in the art would have a reasonable expectation of success because each drug has been used successfully in treating cancer.
Regarding the new limitation “the medicament shows cytotoxicity against a target substance having an expression level of 20,000 molecules or less per cell”, Yip teaches that cetuximab-saporin alone or in combination with PDT showed cytotoxicity in HCT-116 cells (Fig. 3A and 3D). HCT-116 cells express less than 20,000 EGFR per cell, as evidenced by Lennart (see supplemental Table 1 of Dissertation of Lennart, 2023, reproduced below).
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Furthermore, Talaporfin with light irradiation was shown in the art to have cytotoxicity against a target substance (EGFR) having an expression level of 20,000 molecules or less per cell. This is evidenced by Ikeshita (US 2018/0093104A1, pub. date: 4/5/2018). Ikeshita teaches that when irradiated, the cultured MCF7 cells in dish B (with talapofin added) were significantly killed as compared with cultured MCF7 cells in dish A (without talapofin) (Experiment 1). MCF7 cells have an expression level of approximately 15,000 EGFR receptors per cell, as evidenced by Lennart (see supplemental Table 1 of Dissertation of Lennart reproduced above), and the instant specification ([0050]).
Applicant’s Arguments
The response states claim 1 is amended to terminate with the requirement that "the medicament shows cytotoxicity against a target substance having an expression level of 20,000 molecules or less per cell." This recitation is central to claim 1, as discussed in the specification, and its omission from the obviousness analysis means the rejection as applied to claim 1 (and claims 4-5 and 7-8 depending from it) is at least facially incomplete. Applicant therefore respectfully submits that claim 1 is patentably distinct from the cited art at least on this point.
Furthermore, Applicant respectfully disagrees with the asserted combination of art. The rejection is based on an assertion in the Office Action that it would have been obvious to have made a medicament comprising cetuximab-saporin, and talaporfin sodium or porfimer sodium for treating cancer in view of Yip, Baskaran and Lustig, motivated because Yip allegedly teaches cetuximab-saporin can be combined with PDT or PCI for treating cancer, and Baskaran allegedly teaches that talaporfin and porfimer sodium are both second generation photosensitizers and have been approved clinically in treating various cancers. The Examiner considers this as merely combining two compositions each of which being taught by the prior art to be useful for the same purpose, citing In re Kerkhoven. However, such rationale under Kerkhoven requires the components to be interchangeable for the same purpose, and Yip's TPPS2a and Baskaran's talaporfin/porfimer sodium are not shown to be interchangeable as PCI agents. Yip's PCI system is directed to a photosensitizer (TPPS2a) that must localize in endo-lysosomal compartments to rupture membranes and release the immunotoxin into the cytosol, which is not generic PDT, but rather a specific drug delivery system. The Examiner proposes substituting talaporfin sodium or porfimer sodium, described by Baskaran and Lustig as systemic PDT agents used for tissue-level photodestruction into Yip's PCI protocol.
The PCI mechanism in Yip depends on specific endo-lysosomal localization of TPPS2a (Yip, Introduction, pp. 241-242; Figure 1H). On the other hand, Baskaran describes talaporfin's mechanism in terms of standard PDT, that is, intravenous injection, systemic delivery, accumulation in tumor tissue, surface laser irradiation (p. 6). There does not appear to be discussion in Baskaran of endo-lysosomal localization, photochemical internalization (PCI), or any mechanism relating to intracellular drug delivery. Baskaran describes PDT (extracellular/tissue-level photosensitization) not PCI (endo-lysosomal membrane disruption for cytosolic delivery).
Therefore, the Office Action does not establish that talaporfin or porfimer sodium localizes in endo-lysosomal compartments, which is a prerequisite for the PCI function used in Yip. Substituting a systemically-administered PDT agent for an endo-lysosomal PCI agent would arguably change the principle of operation of Yip's system. The Office Action does not point to any statement in Yip, Baskaran, or Lustig expressing a desire or suggestion to substitute talaporfin or porfimer sodium for TPPS2a in a PCI system. The motivation is therefore based retrospectively on improper hindsight reconstruction. Neither Yip nor Baskaran suggests combining these specific components.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive. Regarding the new limitation “the medicament shows cytotoxicity against a target substance having an expression level of 20,000 molecules or less per cell”, Yip teaches that cetuximab-saporin alone or in combination with PDT showed cytotoxicity in HCT-116 cells (Fig. 3A and 3D). HCT-116 cells express less than 20,000 EGFR per cell, as evidenced by Lennart (see supplemental Table 1 of Dissertation of Lennart, 2023, reproduced above).
Furthermore, talaporfin with light irradiation was shown in the art to have cytotoxicity against a target substance (EGFR) having an expression level of 20,000 molecules or less per cell. This is evidenced by Ikeshita (US 2018/0093104A1, pub. date: 4/5/2018). Ikeshita teaches that when irradiated, the cultured MCF7 cells in dish B (with talapofin added) were significantly killed as compared with cultured MCF7 cells in dish A (without talapofin) (Experiment 1). MCF7 cells have an expression level of less than 20,000 EGFR receptors per cell, as evidenced by Lennart (see supplemental Table 1 of Dissertation of Lennart reproduced above), and the instant specification ([0050]).
Applicant’s arguments that Yip's TPPS2a and Baskaran's talaporfin/porfimer sodium are not shown to be interchangeable are not persuasive. Yip discloses that PCI is based on the principles of photodynamic therapy (PDT), which is approved worldwide for different cancer indications (page 244, left column). PDT including PCI uses photosensitizers (PS) which utilizes the absorbed energy from light activation to form reactive oxygen species (ROS) to kill tumor cells (page 244, left column). Baskaran discloses that second generation photosensitizers such as Visudyne (verteporfin), Photofrin (Porfimer sodium) and Laserphyrin (Talaporfin sodium) have been approved clinically and induce tumor regressions. Baskaran discloses that Talaporfin PDT achieved better therapeutic response rate about 80% in over the year (page 6, under subtitle Laserphyrin[Symbol font/0xE2]). Therefore, one skilled in the art would have been motivated to replace TPPS2a of Yip with the photosensitizers of Baskaran for killing tumor cells.
Furthermore, it was known in the art that talaporfin accumulates in endosome/lysosome. Kessel et al (Photochem Photobiol, 2014, 90(4): 889-895) discloses that talaporfin (also known as NPe6) localizes primarily to acidic organelles such as late endosome and lysosomes (page 2, para 2). Osaki et al. (Photodiagnosis and Photodynamic Therapy, 2017, 18:213-220) discloses that NPe6 tends to localize in the lysosomal compartment of cells (page 213, column 1).
Applicant’s arguments that the examiner’s conclusion of obviousness is based on improper hindsight reasoning are not persuasive. MPEP 2145 states "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). In the instant case, Yip teaches cetuximab-saporin can be combined with PDT for treating cancer. Baskaran teaches that second generation photosensitizers (e.g. talaporfin) have improved tissue selectivity and photosensitivity, and are effective and technically superior than first generation PS. (see page 3, right column). In view of the teachings of Yip and Baskaran, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of instant invention and one would have been motivated to have made a medicament comprising cetuximab-saporin, and talaporfin sodium or porfimer sodium for treating cancer.
For the foregoing reasons, the rejection is deemed proper and is therefore maintained.
Double Patenting
8. 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.
9. Claims 1, 4-5 and 7-8 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-38 of copending Application No. 17/913,578 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 9-38 of copending Application No. 17/913,578 (reference application) disclose a method for killing tumor cells using Talaporfin Sodium, Porfimer Sodium or Verteporfin in combination with a conjugate of a substance that binds to a target on the surface of tumor cells and a cytotoxin,
wherein the substance is an antibody, a ligand, or a peptide, and the cytotoxin is saporin, gelonin, or Pseudomonas exotoxin, wherein the tumor cells express EGFR and are cancer cells of any one of head and neck cancer, lung cancer, liver cancer, colorectal cancer, skin cancer, esophageal cancer, stomach cancer, cervical cancer, endometrial cancer, mesothelioma, brain tumor, malignant melanoma, breast cancer, bile duct cancer, pancreatic cancer, ovarian cancer, kidney cancer, bladder cancer, prostate cancer, malignant lymphoma, and osteosarcoma.
Therefore, the claims of copending application disclose a medicament comprising the instantly recited drug components.
10. Claims 1, 4-5 and 7-8 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of copending Application No. 18/694,632 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1-6 of copending Application No. 18/694,632 (reference application) disclose a medicament for killing tumor cells, comprising: a conjugate of a substance that binds to a target substance on the surface of tumor cells and a cytotoxin; and Talaporfin Sodium, Porfimer Sodium or Verteporfin, wherein Talaporfin Sodium, wherein the substance that binds to a target substance on the surface of tumor cells is an antibody, an antibody fragment, a ligand, or a peptide, wherein the cytotoxin is saporin, gelonin, or Pseudomonas exotoxin, wherein the tumor cells are cells that express EGFR, and are cancer cells of any one of head and neck cancer, lung cancer, liver cancer, colorectal cancer, skin cancer, esophageal cancer, stomach cancer, cervical cancer, endometrial cancer, mesothelioma, brain tumor, malignant melanoma, breast cancer, bile duct cancer, pancreatic cancer, ovarian cancer, kidney cancer, bladder cancer, prostate cancer, malignant lymphoma, and osteosarcoma.
Therefore, the claims of copending application disclose every limitation of instant claims.
Applicant’s Arguments
The response states that applicant will consider submitting a terminal disclaimer at such time as the claims are otherwise considered in condition for allowance.
Response to Arguments
The rejections are maintained because applicant has not yet filed a terminal disclaimer.
New Grounds of Objection and Rejection
Claim Objections
11. Claim 7 is objected to for reciting “EGFR, ERBB1” because they refer to same protein.
Claim Rejections - 35 USC § 112
12. 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.
13. Claim 7 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 7 is indefinite for reciting “selected from EGFR, ERBB1, ERBB2, ERBB3, or ERBB4”.
When elements are defined in terms of a list of alternatives ("selected from the group consisting of or selected from”) the use of the conjunction “or” within the list of alternatives results in a lack of clarity with respect to the nature of the individual elements within the list. Since each element forms a part of the group of alternatives, individual elements must be separated grammatically using commas and the inclusive conjunction and, rather than the conjunction or.
The term “or” before “ERBB4” should be changed to “and”.
Conclusion
14. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HONG SANG/Primary Examiner, Art Unit 1646
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