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 .
Priority
This Application is a 371 of PCT/IB2021/058241, filed Sept. 10, 2021, and claims foreign priority to PT116714, filed Sept. 10, 2020 in Portugal.
Claim Status
Claims 1, 4, 7, 9-15, 17, 19-21, 23, and 25-26 are currently pending and subject to examination.
Claim Rejections - 35 USC § 112(d)- Previously Presented
The following is a quotation of 35 U.S.C. 112(d):
“(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
“Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
The rejection of claim 4 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is maintained.
Response to Arguments
The Applicant merely submits that “claim 4 as amended is a proper dependent form” and does not present any arguments as to why.
Reiterated Rejection
Claim 4 does not further limit the method of claim 1 because it recites the mechanism by which the compound of formula (1) treats cancer. Even though the claim was amended to recite that that the “conditions are associated with the inhibition of…”, this is not further limiting to the patient population because the conditions are not actually associated with the inhibition of homologous recombination of DNA repair. The drug acts through this mechanism (Specification, p. 13).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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.
The rejection of claim(s) 1, 4, 7-15, 17, 20-21, 23, and 25-26 under 35 U.S.C. 103 as being unpatentable over Ferreira & Paterna (Phytochemistry Reviews, Vol. 18, p. 971-987, published June 11, 2019) in view of Dhaheri et al. (PLOS ONE, October 2014, Volume 9, Issue 10, e109630, p. 1-14) and Chung et al. (Archives of Pharmaceutical Research, Vol. 28, p. 823-828 (2005)) is maintained.
The rejection of claim(s) 1, 4, 7-15, 17, 19-21, 23, and 25-26 under 35 U.S.C. 103 as being unpatentable over Ferreira & Paterna (Phytochemistry Reviews, Vol. 18, p. 971-987, published June 11, 2019), Dhaheri et al. (PLOS ONE, October 2014, Volume 9, Issue 10, e109630, p. 1-14) and Chung et al. (Archives of Pharmaceutical Research, Vol. 28, p. 823-828 (2005)), as applied to claims 1-4, 7-15, 20-21, 23, and 25-26, and further in view of McCurdy & Cohen (Bioisosterism - Drug Design Org, p. 1-138, published Feb. 2007) is maintained.
Response to Arguments
The Applicant argues that the references do not disclose or suggest treating conditions associated with BRCA1/2-mediated homologous recombination (HR) DNA repair and that the focus on cytotoxicity and MDR modulation would have discouraged a person of ordinary skill in the art from expecting selective targeting of a specific DNA pathway, thereby teaching away from the claimed invention (Remarks, p. 8-9). These arguments were fully considered but are not persuasive. The prior art’s disclosure of the effectiveness of the compounds against colon and liver cancer cell lines does not constitute a teaching away. These are merely alternative cancer types to be treated, and the prior art does not discourage or discredit the teaching of breast cancer:
Furthermore, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) (“a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.”) (internal quotations omitted) (quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023) (“Although Oez [the prior art] used a white pigment with a cross-linking polymer, it does not discourage a skilled artisan from using the white pigment without a cross-linking polymer or lead the skilled artisan in a direction divergent from the path taken in the Appealed Patents. Thus, Oez's disclosure is substantial evidence that supports the Board's finding that Oez does not teach away from the proposed combination.”).
MPEP § 2145(IX)(D)(1).
Moreover, contrary to the Applicant’s assertion that the prior art teaches away from treating cancers such as breast cancer, the prior art actually explicitly suggests that the claimed compounds may be effective in breast cancer through inhibition of breast cancer resistance protein (BCRP):
Breast cancer resistance protein, the latest of drug efflux ABC transporters discovered, which is also involved in MDR of tumours, was first cloned from a doxorubicin-resistant MCF7 breast cancer cell line in Doyle et al. (1998). This protein is characterized by a strong overlap in substrate specificity and tissue distribution with P-gp. It is able to transport a large variety of structurally unrelated compounds that can be neutral, positively or negatively charged. However, it confers resistance to a narrower range of anticancer drugs than P-gp and MRP1. Mitoxantrone and doxorubicin are examples of anticancer agents that are substrates of this protein (Leslie et al. 2005). BCRP has been found to be highly expressed in side-population cells, which are characterized for having stem cell-like properties. Also named as cancer stem cells, they are able to self-renewal and are resistant to chemotherapy and radiotherapy and thus might lead to a relapse after chemotherapy. Therefore, inhibition of BCRP could be important for overcoming multidrug resistance (Wiese 2015). When comparing with P-gp, only a few BCRP inhibitors are known. Among them some flavonoids seem to be promising (Wiese 2015).
Ferreira, col. 2, p. 973.
The Applicant argues that Ferreira does not identify the specific mechanism of action being triggered (Remarks, p. 10-13). These arguments were fully considered but are not persuasive. The Applicant’s amendment to the preamble does not change the scope of the invention. The preamble merely recites a property of the conditions being treated, but does not change the patient population. The claims were originally rejected as being obvious for the treatment of breast cancer. As stated in the non-final action:
Ferreira broadly teaches the claimed compounds for anticancer and anti-drug resistance effects. While Ferreira does not explicitly teach the compounds for the treatment of breast cancer, one of ordinary skill in the art would have a reasonable expectation of success to use the compounds for the treatment of breast cancer because it is commonly known in the art that apoptosis can be induced in breast cancer by reduced Bcl-2 expression and PARP cleavage and that it is desirable to reverse MDR in breast cancer by inhibiting p-glycoprotein. Thus, the compounds of formula (1) would be expected to treat breast cancer in the same way as in the cells lines exemplified by Ferreira.
For example, Dhaheri teaches that plant derived compound carnasol can produces cytotoxic effects in triple negative breast cancer cells (MDA-MB-231) by reducing the expression of bcl2 and reducing PARP cleavage… For example, Chung teaches that it is desirable to inhibit P-gp function drug resistant breast cancer:
Non-final action, p. 5-6.
The Applicant’s argument that the Applicant’s new explanation for the prior art’s functioning in treating cancer (that the drug acts through BRCA1/2-mediated HR DNA repair), does not impart patentability: ““[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999).” (MPEP § 2112(I)).
Reiterated Rejection
Claim(s) 1-4, 7-15, 20-21, 23, and 25-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferreira & Paterna (Phytochemistry Reviews, Vol. 18, p. 971-987, published June 11, 2019) in view of Dhaheri et al. (PLOS ONE, October 2014, Volume 9, Issue 10, e109630, p. 1-14) and Chung et al. (Archives of Pharmaceutical Research, Vol. 28, p. 823-828 (2005)).
Claim 1 is directed towards a method of treating breast cancer, ovarian cancer, endocervical cancer, pancreatic cancer, prostate cancer, lung cancer, glioblastoma or glioblastoma in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (1),
PNG
media_image1.png
146
162
media_image1.png
Greyscale
. The preferred compound of formula (1) is
PNG
media_image2.png
219
188
media_image2.png
Greyscale
(Specification, p. 16).
Ferreira teaches that compounds of formula (1) have utility in the treatment of cancer because they are cytotoxic and combat chemotherapeutic drug resistance.
For example, Ferreira teaches compounds of formula (1), including the preferred compound:
PNG
media_image3.png
408
490
media_image3.png
Greyscale
Ferreira, Fig. 5, p. 979.
Ferreira teaches that these compounds, particularly 24 and 25, have cytotoxic effects in colon cancer and liver cancer cells:
Subsequently, the monoterpene indole and bisindole alkaloids 8–19, isolated from the dichloromethane soluble alkaloid fraction of the methanol extract of the roots of T. elegans, along with dregamine (4) and tabernaemontanine (5) derivatives 20–27, 30 and 31 were evaluated for their ability as apoptosis inducers in HCT116, and SW620 colon and HepG2 liver cancer cells. The cytotoxic effect of the compounds was assessed in the three cell lines by the MTS metabolism and lactate dehydrogenase assays. The apoptosis induction studies included Guava ViaCount flow cytometry assays, nuclear morphology evaluation by Hoechst staining, and caspase-3/7 activity assays. Furthermore, aiming at finding a relationship between the ability of the compounds to inhibit the cell growth and the regulation of cell cycle progression, the cellular DNA content was assessed by flow cytometry, through the analysis of the percentage of cells in different phases of the cell cycle. Moreover, in order to determine the molecular pathways by which compounds exerted their pro-apoptotic effect, crucial apoptosis proteins were evaluated by immunoblot analysis, using total protein extracts from HCT116, SW620 or HepG2 cells exposed to compounds. Among all the tested compounds, the most significant results were obtained for three hydrazones 23–25 and several bisindole alkaloids (8–11 and 14– 16). When analysing structure–activity relationships of compounds 4, 5 and their derivatives (20–27, 30 and 31), it could be deduced that the substitution of the carbonyl group at C-3 of the parent compounds 4 and 5 by a hydrazone moiety, bearing a bromo-pyridine (24 and 25) or a phenyl group (23) might be responsible for their activity. Moreover, the stereochemistry of the tetrahedral stereocenter at C-20 appeared to be also important (Paterna et al. 2015).
Ferreira, p. 979.
Ferreira teaches that the cytotoxic effects are due to “reduced… expression of anti-apoptotic proteins (Bcl-2 and XIAP) and poly(ADP-ribose) polymerase cleavage.” (Ferreira, col. 2, p. 980).
Ferreira also teaches that these compounds can combat multi-drug resistance (MDR) by inhibiting p-glycoprotein and that the compound also synergizes with doxorubicin:
When comparing with dregamine (4) and tabernaemontanine (5), a significant improvement in MDR reversal activity was found for the imine derivatives with an extra aromatic moiety (Paterna et al. 2017) (Table 1). In this way, the highest FAR values were found for the epimeric compounds 24 and 25, bearing 5-bromo-pyridine, and compounds 27 and 32, having pyrazine and 4-methoxybenzyl moieties, respectively. In order to find a correlation between FAR values of compounds in the rhodamine-123 accumulation assay and some physicochemical properties, some molecular descriptors were determined. The strongest inhibitors were characterized with the highest molecular volume, molecular weight (444.6–532.6 g/mol), accessible solvent area and log P values (3.72–5.05).
In drug combination assays, some of these indole alkaloids (22–27, 32, 33, 58–60 and 63) were assayed for their antiproliferative effects in combination with doxorubicin, revealing to synergistically enhance the effect of the antitumor drug, thus indicating that some of these derivatives may be promising leads for overcoming MDR in cancer (Paterna et al. 2017).
Ferreira, p. 982.
Ferreira broadly teaches the claimed compounds for anticancer and anti-drug resistance effects. While Ferreira does not explicitly teach the compounds for the treatment of breast cancer, one of ordinary skill in the art would have a reasonable expectation of success to use the compounds for the treatment of breast cancer because it is commonly known in the art that apoptosis can be induced in breast cancer by reduced Bcl-2 expression and PARP cleavage and that it is desirable to reverse MDR in breast cancer by inhibiting p-glycoprotein. Thus, the compounds of formula (1) would be expected to treat breast cancer in the same way as in the cells lines exemplified by Ferreira.
For example, Dhaheri teaches that plant derived compound carnasol can produces cytotoxic effects in triple negative breast cancer cells (MDA-MB-231) by reducing the expression of bcl2 and reducing PARP cleavage:
Bcl2 family of proteins which includes Bcl2, and bcl-2 related members such as Bax, plays a crucial role in regulation apoptosis. Therefore, we decided to test the effect of carnosol on the expression level of the anti-apoptotic Bcl2, and pro-apoptotic Bax, proteins. As it is shown in figure 3B (lower panel), carnosol reduced, in dose dependent manner, the level of Bcl2 while increased the level of Bax in MDA-MB-231 cells leading to an increase in the Bax/Bcl2 ratio which is in favor for apoptosis induction.
Dhaheri, p. 6;
Next, we investigated whether the observed growth inhibition upon carnosol treatment was associated with induction of apoptosis. Following 24 hours of treatment, annexin V staining was detected in cells treated with 50 and 100 µM of carnosol (Figure 3A), indicating that these cells are undergoing apoptosis. No necrotic cells were detected at both concentrations. No Annexin V stain was detected at lower concentration (25 µM), indicating absence of apoptosis which is in agreement with the cell viability data. In order to determine the apoptotic pathway induced by carnosol in MDA-MB-231 cells, activation of caspase 3, 8 and 9 along with PARP cleavage was assessed by Western blotting. As it is shown in figure 3B, cleaved PARP and cleaved caspase 3, 8 and 9 increased in concentration-dependent (50 and 100 µM) manner in carnosol-treated cells. Again, neither caspase activation nor PARP cleavage was detected in cells treated with 25 µM carnosol for 24 h.
Dhaheri, p. 5-6.
For example, Chung teaches that it is desirable to inhibit P-gp function drug resistant breast cancer:
Multidrug resistance (MDR) is one of the most significant obstacles in cancer chemotherapy. One of the mechanisms involved in the development of MDR is the over-expression of P-glycoprotein (P-gp). It is widely known that natural compounds found in vegetables, fruits, plant derived beverages and herbal dietary supplements not only have anticancer properties, but may also modulate P-gp activity. Therefore, the purpose of this investigation was to examine the effects of naturally occurring products on P-gp function in human breast cancer cell lines, MCF-7 (sensitive) and MCF-7/ADR (resistant). The accumulation of daunomycin (DNM), a Pgp substrate, was greater in the sensitive cells compared to the resistant cells, while the efflux of DNM was higher in the resistant cells compared to the sensitive cells over a period of 2 h...These results suggest that some flavonoids such as biochanin A and silymarin may reverse MDR by inhibiting the P-gp function.
Chung, Abstract.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claims 4 is directed towards the method of claim 1, wherein the conditions are associated with the inhibition of homologous recombination DNA repair through disruption of BRCA1-BARD1 interaction, respectively.
These inhibition of HR DNA repair is an inherent properties of the compound of formula (1). Therefore, these events would necessarily occur from the administration of the compounds to a patient. Thus, claims 4 is rejected on the same grounds as claim 1 and was prima facie obvious at the time of filing.
Claim 7 is directed towards a method of treating triple-negative breast cancer in a patient comprising administering to the patient a therapeutically effective amount of the compound of general formula (1):
PNG
media_image1.png
146
162
media_image1.png
Greyscale
. The preferred compound of formula (1) is
PNG
media_image2.png
219
188
media_image2.png
Greyscale
(Specification, p. 16).
One of ordinary skill in the art would have a reasonable expectation of success to treat triple negative breast cancer with the compound of formula (1) because as shown in the rejection of claim 1, Ferreira teaches that the compound of formula (1), particularly the preferred compound, exerts cytotoxic effects in cancer cells by reducing the expression of proapoptotic proteins including bcl-2 and inhibiting PARP cleavage and it is commonly known in the art that by reducing the expression of proapoptotic proteins including bcl-2 and inhibiting PARP cleavage can also kill triple negative breast cancer cells as shown by Dhaheri. The rejection of claim 1 is incorporated herein by reference.
Therefore, claim 7 was prima facie obvious at the time of filing.
Claims 9-15, 17, 20-21 and 23 are directed towards the method of claim 1, and read on the compound
PNG
media_image2.png
219
188
media_image2.png
Greyscale
(Specification, p. 16). The rejection of claim 1 is incorporated herein by reference.
Therefore, claims 9-15, 17, 20-21 and 23 were prima facie obvious at the time of filing.
Claim 25 is directed towards a method of treating breast cancer, ovarian cancer, endocervical cancer, pancreatic cancer, prostate cancer, skin cancer, lung cancer, glioblastoma, or neuroblastoma in a patient comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically effective carrier and a therapeutically effective amount of a compound of general formula (1),
PNG
media_image1.png
146
162
media_image1.png
Greyscale
. Claim 26 is directed towards the method of claim 25, wherein the pharmaceutical composition further comprises an additional chemotherapeutic agent.
One of ordinary skill in the art would have a reasonable expectation of success to treat cancer, including breast cancer, with a pharmaceutical composition comprising the compound of formula (1) and an additional chemotherapeutic agent because as shown in the rejection of claim 1, Ferreira teaches that compounds of general formula (1) combat MDR and synergize with chemotherapeutic agents like doxorubicin and it is known that this is desirable for the treatment of drug resistant breast cancer, as shown by Chung. The rejection of claim 1 is incorporated herein by reference.
Therefore, claims 25-26 were prima facie obvious at the time of filing.
Claim(s) 1, 4, 7-15, 17 19-21, 23, and 25-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ferreira & Paterna (Phytochemistry Reviews, Vol. 18, p. 971-987, published June 11, 2019), Dhaheri et al. (PLOS ONE, October 2014, Volume 9, Issue 10, e109630, p. 1-14) and Chung et al. (Archives of Pharmaceutical Research, Vol. 28, p. 823-828 (2005)), as applied to claims 1-4, 7-15, 17, 20-21, 23, and 25-26, and further in view of McCurdy & Cohen (Bioisosterism - Drug Design Org, p. 1-138, published Feb. 2007).
The rejection of claims 1-4, 7-15, 17, 20-21, 23, and 25-26 under 35 U.S.C. 103 above is incorporated herein by reference.
Claim 19 is directed towards the method of claim 1, wherein R7 is C1-C6 alkyl, C1-C6 alkenyl or C1-C6 alkynyl.
As shown above, Ferreira teaches a compound of formula (1), wherein R5 is C(O)-O-methyl. While Ferreira does not teach a compound of formula (1) wherein R5 is CONH-Methyl as in claim 19, one of ordinary skill in the art would have a reasonable expectation of success to replace C(O)-O-methyl with CONH-Methyl because it is commonly known in the art that these are bioisosteres with similar properties. For example, McCurdy teaches:
PNG
media_image4.png
328
666
media_image4.png
Greyscale
McCurdy, p. 7.
Therefore, claim 19 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 86-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
Prosecution Insights