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 .
DETAILED ACTION
Claims 5-7, 9-11 and 16-24 are pending in the application. Claims 5-7, 9-11 and 16-24 are rejected.
Election/Restrictions
Applicant's election with traverse of the species of the first compound recited in claim 10 in the reply filed on April 6th, 2026 is acknowledged. The traversal is on the ground(s) regarding the procedures following an election of species rather than the basis for requiring an election of species. This is not found persuasive because it does not address the propriety of the restriction requirement itself.
The requirement is still deemed proper and is therefore made FINAL.
As per MPEP 803.02, the examiner will determine whether the entire scope of the claims is patentable. Applicants' elected species is not allowable. MPEP 803.02 states:
Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability. […]
If the Markush claim is not allowable, the provisional election will be given effect and examination will be limited to the Markush claim and claims to the elected species, with claims drawn to species patentably distinct from the elected species held withdrawn from further consideration. […]
If on examination the elected species is found to be anticipated or rendered obvious by prior art, the Markush claim and claims to the elected species will be rejected, and claims to the nonelected species will be held withdrawn from further consideration.
As the elected species has been found not allowable, the Markush-type claims have been rejected and claims to the nonelected invention held withdrawn from further consideration. Claims 5-7, 9-11 and 16-24 have been examined to the extent that they are readable on the elected embodiment. Since the elected species is not allowable, subject matter not embraced by the elected embodiment is therefore withdrawn from further consideration.
Additional prior art issues were discovered incidental to the search of the elected species and are presented below in the interest of compact prosecution.
Information Disclosure Statement
The Examiner has considered the Information Disclosure Statement(s) filed on October 25th, 2023 (two), and February 13th, 2025 (one).
The information disclosure statement filed February 13th, 2025 that cites foreign applications fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
Improper Markush Grouping
The nonstatutory Markush grouping rejection is based on a judicially approved “improper Markush grouping” doctrine. A Markush claim contains an “improper Markush grouping” if: (1) The species of the Markush group do not share a “single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent. When an examiner determines that the species of a Markush group do not share a single structural similarity or do not share a common use, then a rejection on the basis that the claim contains an “improper Markush grouping” is appropriate. See the Federal Register, Vol. 76, No. 27, dated February 9, 2011, page 7166.
Claims 10 and 19-24 are rejected under improper Markush grouping as the claims contain an improper grouping of alternatively useable species.
In the present case, at least (1) applies. It cannot be said that all members of the Markush group have a single structural similarity. The four structures do not share any particular functional groups or ring structures in common where three of the four contain significantly different heterocyclic rings and the last contains a carbocyclic ring. These varying functional groups are not recognized to belong to the same physical or chemical class or to the same art-recognized class. For example, in CPC classification, compounds having two fused heterocycles (as in compound NSC 682769) are classified in C07D 487/02. Compounds having no heterocycles but an amide (as in NSC 90673) are classified in C07C 233/14. Compounds having a six-membered ring with a nitrogen atom condensed with additional rings (as in NSC627650) are classified in C07D 221/18. Compounds having a triazine ring (as in NSC 627650) are classified in C07D 251/54.
Therefore, it cannot be said that all members of the Markush group have a single structural similarity with respect to the functional groups present and the claims therefore are considered to contain an “improper Markush grouping”.
Claim Rejections - 35 USC § 112(b)
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 5 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 5 recites the limitation "the subject" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 5 does not previously recite “a subject” and it is unclear which qualifiers or properties must be possessed by “the subject”.
Claim Rejections - 35 USC § 102
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.
Claim(s) 5 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Link et al. J. Med. Chem. 1998, 41, 1299-1305 and its supporting information.
Link et al. teach compounds of the following general formula on page 1300:
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The prior art teaches compound 10n on the same page as follows:
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The compound corresponds to Applicant’s elected species. The prior art further teaches that the compound was tested in cancer cell lines on page 1300:
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The supporting information indicates that compound 10n was tested. Accordingly, the prior art teaches contacting a cell with the instant elected species. The limitation of “inhibiting tumor growth” is considered an intended use or intended outcome that does not materially distinguish from the active step otherwise taught by the prior art. Furthermore, the property of “capable of inhibiting…” is considered an inherent property of the compound itself.
Claim(s) 5 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu-Chittenden et al. Genes & Development 2012, 26, 1300-1305.
The prior art teaches verteporfin (VP) inhibits YES-TEAD binding on page 1303: “Thus, we identified VP and PPIX as the first small molecule inhibitors targeting the physical interactions between YAP and TEAD.” The prior art teaches the following assay on pages 1304 and 1305:
[…] In the second assay, we tested VP in mice bearing liver-specific knockout of NF2/ Merlin, which exhibited bile duct overproliferation due to activation of endogenous YAP (Zhang et al. 2010). Pregnant mothers bearing Alb-Cre; Nf2flox2/flox2 embryos received VP injections (100 mg/kg) every other day starting at embryonic day 9 (E9) of the Alb-Cre; Nf2flox2/flox2 embryos until birth (Fig. 4D), and BECs were visualized by CK staining at E18.5. As shown in Figure 4E, the number of CK-positive BECs was significantly reduced in VP-treated Nf2-deficent livers compared with control-treated Nf2-deficient livers. Thus, VP suppressed liver overgrowth resulting from either YAP overexpression or activation of endogenous YAP. […]
The limitation of “inhibiting tumor growth” is considered an intended use or intended outcome that does not materially distinguish from the active step otherwise taught by the prior art. Furthermore, the property of “capable of inhibiting…” is considered an inherent property of the compound itself where the prior art teaches that verteporfin interferes with the YAP-TEAD complex. Regarding the limitation of “reducing YAP levels,” Liu-Chitten et al. teach on page 1304: “In addition, VP dose-dependently accelerated trypsin cleavage of YAP with an EC50 (half maximal effective concentration) value of 0.1 mM (Fig. 3E). These results suggest that VP binds to YAP and enhances the accessibility of trypsin to YAP, presumably by changing the conformation of YAP.”
Claim(s) 5 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Al-Moujahed et al. Scientific Reports, 2017, 7:7602, pages 1-8.
Al-Moujahed et al. teach contacting human glioma cells with verteporfin as follows on page 3:
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The prior art further teaches verteporfin as affecting the YAP-TEAD complex on page 2: “Recent studies have shown that VP may disrupt the YAP-TEAD complex and inhibit growth of hepatocellular carcinoma and ovarian cancer without light activation10, 30.” The limitation of “inhibiting tumor growth” is considered an intended use or intended outcome that does not materially distinguish from the active step otherwise taught by the prior art. Furthermore, the property of “capable of inhibiting…” is considered an inherent property of the compound itself where the prior art teaches that verteporfin interferes with the YAP-TEAD complex.
Claim(s) 19-23 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Steinhardt et al. Hum. Pathol. 2008, 39, 1582-1589.
Steinhardt et al. teach the following general method in the abstract:
[…] YAP expression intensity and distribution were evaluated in normal tissues and compared to the most frequently occurring malignant tumors in these tissues (colonic adenocarcinoma, lung adenocarcinoma, ovarian serous cystadenocarcinoma, and ductal carcinoma of the breast). For each tissue, the nuclear and cytoplasmic YAP expression intensity was scored as negative, low, or high. […]
Regarding breast cancer (recited in instant claim 20 and further embraced by instant claim 21 that does not limit the scope of cancer to brain cancer), Steinhardt et al. teach obtaining samples according to instant step a) of claim 19 (and further embraced by instant claim 22) on page 5 as follows:
Nuclear and cytoplasmic YAP expression was assessed in 49 patients with normal breast tissue biopsies and in neoplastic tissues of DCB. […]
Steinhardt et al. further teach measuring the level of YAP and note the following findings:
[…] In the group with normal breast tissue, 11 of 14 (43%+36% = 79%) patients expressed nuclear YAP in the ductal epithelium
compared to 33 of 35 (85%+11% = 94%) patients with DCB tissue (figure 3 “breast”). There was no statistically significant difference in any detectable nuclear YAP expression between the normal breast and DCB tissue (p=0.13). […]
In those patients with normal breast tissue, 14 of 14 (100%) patients expressed cytoplasmic YAP in the ductal epithelium while 34 of 35 (68%+29%=97%) patients with DCB tissue had any detectable cytoplasmic YAP expression (figure 4 “breast”). The cytoplasmic YAP expression difference between the normal breast and DCB tissues was not statistically significant (p=0.29) even when we compared the cytoplasmic YAP expression across the distribution of intensities for normal and DCB tissues.
The prior art teaches multiple embodiments where YAP levels do not differ significantly from normal breast tissue (that can be considered a control). Furthermore, instant claim 19 does not require an active step of actually obtaining a control sample and does not define any particular level of YAP that must be found in the control sample. Accordingly, it would appear that any level of YAP could serve as the differentiating level between the alternatives of instant step c). The decision aspect of step c) of claim 19 is considered a mental step that does not materially distinguish from the active steps of the prior art, i.e. where the prior art demonstrates a level of YAP that can be considered the same as a control sample and where a composition comprising any of the four depicted compounds in claim 19 was not administered to the patients. Furthermore, the instant claim 19 only requires the steps to be performed relative to “a cancer patient” rather than some sample size greater than one where patients are treated differently. Regarding instant claim 23, this claim would only appear to limit embodiments where the composition comprising one of the four compounds is administered rather than exclude embodiments where the composition is not administered.
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.
Claim(s) 5, 6, 9, 11 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Al-Moujahed et al. Scientific Reports, 2017, 7:7602, pages 1-8.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Al-Moujahed et al. teach contacting human glioma cells with verteporfin as follows on page 3:
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The prior art further teaches verteporfin as affecting the YAP-TEAD complex on page 2: “Recent studies have shown that VP may disrupt the YAP-TEAD complex and inhibit growth of hepatocellular carcinoma and ovarian cancer without light activation10, 30.” The limitation of “inhibiting tumor growth” is considered an intended use or intended outcome that does not materially distinguish from the active step otherwise taught by the prior art. Furthermore, the property of “capable of inhibiting…” is considered an inherent property of the compound itself where the prior art teaches that verteporfin interferes with the YAP-TEAD complex.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art anticipates instant claim 5 where anticipation is the epitome of obviousness. Instant claims 5 and 6 additionally encompass embodiments where the compound is administered to a human subject. Additional limitations of dependent claims are addressed below.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2141.02)
Al-Moujahed et al. teach in the abstract: “This study suggests that verteporfin should be further explored as an adjuvant therapy for the treatment of glioblastoma.” Accordingly, a person having ordinary skill in the art in seeking to expand the study of Al-Moujahed et al. would have been motivated to administer verteporfin to a subject having glioblastoma. Regarding instant claim 9, the limitation of “has been identified…” appears to be a mental step; however, at least since the prior art teaches that (abstract) “we identified that human glioma cells that were exposed to VP without light activation demonstrated a downregulation of YAP-TEAD-associated downstream signaling molecules,” a person having ordinary skill in the art would have been motivated to treat patients having elevated YAP levels. Regarding instant claim 11, at least since the prior art teaches treatment (as opposed to prevention), a person having ordinary skill in the art would have been motivated to administer verteporfin to patients already diagnosed with glioblastoma. Regarding instant claim 16, the prior art teaches activity in human cell lines on page 3 such that a person having ordinary skill in the art would have been motivated to treat human patients.
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Al-Moujahed et al. Scientific Reports, 2017, 7:7602, pages 1-8, as applied to claims 5, 6, 9, 11 and 16 above, in view of Davis, E. D. Clin. J. Oncol. Nurs. 2016, 20, S2-S8.
Al-Moujahed et al. teach application of verteporfin (abstract): “as an adjuvant therapy for the treatment of glioblastoma.” Davis teaches on pages 3 and 4: “Treatment of newly diagnosed GBM requires a multidisciplinary approach. Current standard therapy includes maximal safe surgical resection, followed by concurrent radiation with temozolomide (TMZ) (Temodar®), an oral alkylating chemotherapy agent, and then adjuvant chemotherapy with TMZ (National Comprehensive Cancer Network [NCCN], 2015).” It would have been prima facie obvious for one of ordinary skill in the art at the time the invention was made to co-administer two compounds/compositions known in the prior art which are taught to be useful for the same purpose. "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). Thus, the skilled artisan would reasonably expect success in this combination.
Claim(s) 17 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Al-Moujahed et al. Scientific Reports, 2017, 7:7602, pages 1-8, as applied to claims 5, 6, 9, 11 and 16 above, in view of Michy et al. Cancers 2019, 11, 1760.
Al-Moujahed et al. teach application of verteporfin (abstract): “as an adjuvant therapy for the treatment of glioblastoma.” The authors, however, do not teach how verteporfin should be administered accordingly to claims 17 and 18. Al-Moujahed et al. teach on page 2: “More recently, PDT has also been experimentally used as a light-based therapeutic modality for several human malignancies13–17.” A person having ordinary skill in the art would have at least been motivated to test modes of administration that have been successfully applied with verteporfin. For instance, Michy et al. teach in the abstract: “In contrast, laser light exposure of tumors after intravenous administration of NLC-verteporfin (8 mg·kg−1) significantly inhibited tumor growth without visible toxicity. NLC-verteporfin thus led to efficient verteporfin vectorization to the tumor site and protection from side-effects, providing promising therapeutic prospects for photodynamic therapy of cancer.” Accordingly, a person having ordinary skill in the art would have at least been motivated to test intravenous administration as embraced by instant claims 17 and 18 as the prior art teaches that it is useful in delivering verteporfin to cancer cells.
Claim(s) 19-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Steinhardt et al. Hum. Pathol. 2008, 39, 1582-1589 in view of Kole et al. Scientific Reports 2019, 9, 9934, pages 1-9.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Steinhardt et al. teach the following general method in the abstract:
[…] YAP expression intensity and distribution were evaluated in normal tissues and compared to the most frequently occurring malignant tumors in these tissues (colonic adenocarcinoma, lung adenocarcinoma, ovarian serous cystadenocarcinoma, and ductal carcinoma of the breast). For each tissue, the nuclear and cytoplasmic YAP expression intensity was scored as negative, low, or high. […]
Regarding breast cancer (recited in instant claim 20 and further embraced by instant claim 21 that does not limit the scope of cancer to brain cancer), Steinhardt et al. teach obtaining samples according to instant step a) of claim 19 (and further embraced by instant claim 22) on page 5 as follows:
Nuclear and cytoplasmic YAP expression was assessed in 49 patients with normal breast tissue biopsies and in neoplastic tissues of DCB. […]
Steinhardt et al. further teach measuring the level of YAP and note the following findings:
[…] In the group with normal breast tissue, 11 of 14 (43%+36% = 79%) patients expressed nuclear YAP in the ductal epithelium
compared to 33 of 35 (85%+11% = 94%) patients with DCB tissue (figure 3 “breast”). There was no statistically significant difference in any detectable nuclear YAP expression between the normal breast and DCB tissue (p=0.13). […]
In those patients with normal breast tissue, 14 of 14 (100%) patients expressed cytoplasmic YAP in the ductal epithelium while 34 of 35 (68%+29%=97%) patients with DCB tissue had any detectable cytoplasmic YAP expression (figure 4 “breast”). The cytoplasmic YAP expression difference between the normal breast and DCB tissues was not statistically significant (p=0.29) even when we compared the cytoplasmic YAP expression across the distribution of intensities for normal and DCB tissues.
The prior art teaches multiple embodiments where YAP levels do not differ significantly from normal breast tissue (that can be considered a control). Furthermore, instant claim 19 does not require an active step of actually obtaining a control sample and does not define any particular level of YAP that must be found in the control sample. Accordingly, it would appear that any level of YAP could serve as the differentiating level between the alternatives of instant step c). The decision aspect of step c) of claim 19 is considered a mental step that does not materially distinguish from the active steps of the prior art, i.e. where the prior art demonstrates a level of YAP that can be considered the same as a control sample and where a composition comprising any of the four depicted compounds in claim 19 was not administered to the patients. Furthermore, the instant claim 19 only requires the steps to be performed relative to “a cancer patient” rather than some sample size greater than one where patients are treated differently. Regarding instant claim 23, this claim would only appear to limit embodiments where the composition comprising one of the four compounds is administered rather than exclude embodiments where the composition is not administered.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art anticipates instant claims 19-23 where anticipation is the epitome of obviousness. Instant claim 24 additionally encompasses embodiments where a chemotherapeutic agent is administered.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
At least since Steinhardt et al. teach that the subjects of the study had ductal carcinoma of the breast (DCB), a person having ordinary skill in the art in seeking to actually treat the condition of the subjects would have been motivated to administer typical treatment approaches. For instance, Kole et al. provide a study on subjects having invasive ductal carcinoma alone or with ductal carcinoma in situ. The authors note on page 3: “The majority of patients received radiation therapy (65.9%) and hormonal therapy (73.7%). Approximately one half of patients (48.9%) received chemotherapy.” Accordingly, a person having ordinary skill in the art in seeking to treat the subjects of Steinhardt et al. and/or expand the study to include additional subjects would been motivated to treat the subjects with therapies including chemotherapy.
Conclusion
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/MATTHEW P COUGHLIN/Primary Examiner, Art Unit 1626
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