DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
The amendment filed on 2/27/2026 in response to the non-final rejection of 10/27/2025 is acknowledged and has been entered.
Claims 1-5, 9-13, 15-16, 21 and 31-33 are currently pending.
Applicant’s election without traverse of Group 1, claims 1-13 and 15-17 in the reply filed on 9/30/2025. Applicants further election of selenocystine as the Category 1 or Category 2 compound and diphenyl diselenide as the Category 3, 4 or 5 compound is acknowledged. After a review of the prior art, the species election for the category 1 and category 2 compounds have been expanded to include a number of the “category 1” compounds recited in claim 9. Moreover, selenomethionine as recited in claim 12 has been included in the species election of a category 4 compound. As such, claim 6, 9 and 12 have been included in examination. Note: Upon reviewing the arguments, the examiner has expanded the species election to also encompass sulphoraphane, e.g. sulforaphane.
Accordingly, claims 1-5, 9-13 and 17 read on the elected species/invention.
Claims 21 and 31-33 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/30/2025.
Claims 15-16 are withdrawn from consideration as being drawn to nonelected species.
Rejections Withdrawn
The rejection Claims 1-6, 7-8, 11, 13 and 17 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. Specifically, The term “category 1, 2, 3, 4 or 5” in claim 1 is a relative term which renders the claim indefinite is withdrawn in view of Applicants amendments.
The rejection of claim 1, 7-8, 10 and 17 under 35 U.S.C. 102a(1) as being anticipated by SELEQ OY (WO 2019/224428A1, 2019-11-28) referred to herein as SELEQ is withdrawn in view of Applicants amendments.
Rejections Maintained, but amended in view of Applicants amendments:
Response to Amendment
The declaration under 37 CFR 1.132 filed on 2/27/2026 by Sougat Misra is insufficient to overcome the rejection of claims 1-9, 11-13 and 17 based upon the rejections under 35 U.S.C. 103 as being unpatentable over Pomeranian Academy of Medicine (WO2005/013951A2, 2005-02-17) alone or in combination with Barbosa et al. (Arch Toxicol (2008) 82: 655-663) as set forth in the previous office action.
In response to the rejection, the Declarant asserts that the data provided in the specification,
as filed, and the additional data provided herein, the claimed combination of a cytotoxic agents and a cytotoxic agents resulted in a synergistic cytotoxic effect that was unexpected. Specifically, the Declarant summarize the various cytotoxicity experiments performed within the specification and shown in figures 1-7 and Tables 1-5, which the Declarant asserts demonstrates the results of different experiments showing the unexpected results of the combination of a cytotoxic agent(s) and cytotoxicity enhancing agents. Note: In order to be concise, the Examiner is only providing a brief summary of Declarants explanation.
-Table 1 shows IC50 values for diphenyl diselenide and 6 other small molecules asserted to be (cytotoxic enhancing molecules) in leukemia, lung and breast cancer cell lines.
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-Table 2 shows the IC50 values of sodium selenite and selenocystine either alone or in combination with diphenyl diselenide in a number of different cells lines wherein the range of “fold-increase” by the combination was 1.61 to 402.6 for sodium selenite and 0.79 to 102.6 for selenocystine. The Declarant makes a note here that an increase in cytotoxicity (e.g. decrease in IC50) does not mean synergistic effects.
-Table 3 shows the IC50 values of sodium selenite either alone or in combination with other cytotoxicity enhancing compounds in different cell lines.
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-Table 4 shows the IC50 values of selenocystine either alone or in combination with other cytotoxicity enhancing compounds in different cell lines.
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-Figures 6A and 7B shows the combination of either sodium selenite or selenocystine with diphenyl diselenide leads to synergistic cytotoxic effects in HL60 cells (leukemia cell line).
Declarants further provides evidence of synergistic effects of diphenyl diselenide when used in combination either sodium selenite or selenosystine using the Chou-Talalay method which is a common approach for drug-drug interaction analysis in pharmacology. Specifically, diphenyl selenide was used as the cytotoxicity enhancing agent to calculate ZIP scores in lung cancer cell line (HI299) and leukemia cell line (HL60), wherein a positive Zip Score >10 represents synergy, -10 to 10 is additive, <-10 is antagonism.
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Moreover, Declarant notes that these 3D plots clearly demonstrates that the molar ratio of non-toxic cytotoxicity enhancing small molecule to the cytotoxicity-inducing small molecule is an important factor to achieve better cancer killing effect, wherein the ratio is important for intended clinical application.
The Declarant summarizes a number of mechanistic studies from the specification used to test whether selenite-induced cell death can be abrogated in the presence of diphenyl selenide (DPDS).
Note: The Declarant provides an explanation of the groupings brought up in the 112 2nd rejection set forth in the previous office action which is moot in view of the rejection being withdrawn in view of Applicants amendment.
These arguments have been carefully considered, but are not found persuasive.
First, the Examiner appreciates the Declarants analysis of the specific examples within the specification. Regarding the assertions made in the declaration, the Examiner would like to first point out that at least claim 1 is drawn to a pharmaceutical composition comprising at least one cytotoxic agent and at least one cytoxicity enhancing agent. In view of this, the claims do not require that the pharmaceutical composition only be used for the treatment of cancer or a specific type of cancer which the Declarant or Applicants have shown synergy within. This is different than if Applicants were claiming a method of treating a specific type of cancer with the claimed pharmaceutical composition which has shown synergy. For example, Wang et al. (Nutrition Research 2015; 35: 610-617) teaches synergy between sulforaphane and selenium (Sodium Selenite)in protection against oxidative damage in colonic CCD841 cells (normal colon cells) (Title and Abstract). As such, a pharmaceutical composition comprising sulforaphane (a cytotoxic enhancing agent (see claim 12)) and sodium selenite (a cytotoxic agent (see claim 9) which reads on at least claim 1 can be reasonably expected to protect normal cells from oxidative stress. Regarding the unexpected results, the Examiner acknowledges and is impressed with the fold increase in many of the cancer cells in Table 2 which is the combination of sodium selenite or selenocystine and diphenyl diselenide (DPPS). However, the Examiner is less impressed with the combination of sodium selenite or selenocystine and the other asserted cytotoxic enhancing agents as there seems to be many instances where they did not appear to work, e.g. enhance cytotoxicity (blank spaces for the combination). Moreover, it is unclear how much of the “other compounds” were given and their impact alone on the cell lines. Regarding specifically the unexpected results, the Examiner recognizes that it is unclear whether these are truly unexpected or reasonably expected. For example, Zhang et al. (Chemical Research in Toxicology 2013; 26:456-464) found that organoselenium compounds modulate extracellular redox by induction of extracellular cysteine and cell surface thioredoxin reductase (Title). Specifically, Zhang et al. found that arylselenium compounds benzeneselenol (PhSeH), dibenzyl diselenide (DBDSe), diphenyl diselenide (DPDSe) and ebselen were capable of inducing extracellular cysteine accumulation via a cystin- and glucose-dependent processes, wherein extracellular cysteine production was dose-dependently inhibited by glutamate, an inhibitor of cystine/glutamate antiporter (Xc- transporter) supporting the involvement of Xc- transporter for cystine uptake in the above process (abstract). Note: Xc- transporter appears to be also referred to as SLC7A11 in the art. Moreover, Zhang et al. also found that DPDSe synergized with sodium selenite leading to the dramatic inhibition of cell proliferation in Hepa Iclc7 (hepatoma cells) and RAW 264.7 cells (mouse tumor induced by Abelson murine leukemia virus) and suggests that this cotreatment may extend to the combination of other organoselenium compounds with sodium selenite (page 462, 2nd column 2, 2nd full paragraph). As such, there appears to be some reasonable expectation that such results would be expected. Assuming, arguendo, that Applicants have shown unexpected results, the claims do not appear to be commensurate in scope with the results presented. First, the claims are broad (see below). Secondly, the claims do not require any molar ratio which as noted by the Declarant is an important factor to achieve better cancer cell killing effect. As such, the rejection set forth below is maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-5, 9, 12 and 17 remain rejected under 35 U.S.C. 103 as being unpatentable over Pomeranian Academy of Medicine (WO2005/013951A2, 2005-02-17) referred to herein as Pomeranian.
Pomeranian teach pharmaceutical compositions of selenium (or its salts or derivatives or any other selenium comprising compound) and a method of using said pharmaceutical composition for the prevention of breast /ovarian cancers (abstract). With regards to the selenium, Pomeranian teach selenium or its salts or derivatives refers to any known selenium comprising compound including, but not limited to, elemental selenium, selenium dioxide, selenoic acid, potassium selenide, calcium selenite, selenomethinine and dimethyl selenide, wherein the selenium or its salts or derivates can be used in conjunction with other selenium containing compounds (page 5, last paragraph bridging page 6). Pomeranian further teach that the pharmaceutical composition comprises a pharmaceutically acceptable carrier in in addition to the compound(s) of the invention (page 7, 1st full paragraph). Moreover, Pomeranian teach that the compounds of the invention may be administered in conjunction with one or more other known antineoplastic and/or cancer preventative agents either together or sequentially page 7, last paragraph bridging page 8).
While Pomeranian contemplates treating cancer using a selenium compound with other selenium compounds and/or anti-neoplastic agents either together or sequentially, Pomeranian does not explicitly teach a pharmaceutical composition comprising a combination or the ratio’s present within the composition.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the pharmaceutical composition taught by Pomeranian to include another selenium or anti-neoplastic agent for treatment of cancer. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Pomeranian contemplates treating cancer using a selenium compound with other selenium compounds and/or anti-neoplastic agents either together or sequentially.
- "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.).
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to optimize the ratio’s of selenium compound to the other agents within the pharmaceutical composition for the treatment of cancer. One of ordinary skill in the art would have been motivated to make such an optimization, with a reasonable expectation of success, because:
- Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
While the prior art does not specifically teach the results obtained of administering the pharmaceutical composition as recited in claim 2-4, the claimed limitation does not appear to result in a manipulative difference in the optimization of the amounts or ratios as set forth above for the treatment of cancer. "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Claim(s) 1-5, 9, 11-13 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pomeranian Academy of Medicine (WO2005/013951A2, 2005-02-17) referred to herein as Pomeranian, in view of Barbosa et al. (Arch Toxicol (2008) 82: 655-663).
Pomeranian teach pharmaceutical compositions of selenium (or its salts or derivatives or any other selenium comprising compound) and a method of using said pharmaceutical composition for the prevention of breast /ovarian cancers (abstract). With regards to the selenium, Pomeranian teach selenium or its salts or derivatives refers to any known selenium comprising compound including, but not limited to, elemental selenium, selenium dioxide, selenoic acid, potassium selenide, calcium selenite, selenomethinine and dimethyl selenide, wherein the selenium or its salts or derivates can be used in conjunction with other selenium containing compounds (page 5, last paragraph bridging page 6). Pomeranian further teach that the pharmaceutical composition comprises a pharmaceutically acceptable carrier in in addition to the compound(s) of the invention (page 7, 1st full paragraph). Moreover, Pomeranian teach that the compounds of the invention may be administered in conjunction with one or more other known antineoplastic and/or cancer preventative agents either together or sequentially page 7, last paragraph bridging page 8).
While Pomeranian contemplates treating cancer using a selenium compound with other selenium compounds and/or anti-neoplastic agents either together or sequentially, Pomeranian does not explicitly teach that the second selenium compound is diphenyl diselenide or the ratio’s present within the composition.
Barbosa et al. teach that diphenyl diselenide is a synthetic organoselenium compound that possess glutathione peroxidase-like activity and exhibits antioxidant, anti-hyperglycemic and anti-inflammatory properties, wherein when used in pharmacological doses it has low toxicity in rodents (page 656, 1st column, 2nd full paragraph). Moreover, Barbosa et al. teach that diphenyl diselenide can retard cancer development and may be considered as a potential chemopreventitive agent (page 661, 2nd column, last paragraph bridging page 662).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the pharmaceutical composition taught by Pomeranian to include diphenyl diselenide as the another selenium compound or anti-neoplastic agent/chemo-preventative agent for treatment of cancer in view of Barboasa. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
- Barbosa et al. teach that diphenyl diselenide can retard cancer development and may be considered as a potential chemopreventitive agent.
- "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.).
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to optimize the ratio’s of selenium compound to the other agents within the pharmaceutical composition for the treatment of cancer. One of ordinary skill in the art would have been motivated to make such an optimization, with a reasonable expectation of success, because:
- Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
While the prior art does not specifically teach the results obtained of administering the pharmaceutical composition as recited in claim 2-4, the claimed limitation does not appear to result in a manipulative difference in the optimization of the amounts or ratios as set forth above for the treatment of cancer. "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
In response to this rejection, Applicants contend that Pomeranian fails to disclose or suggest the combination as claimed and that Barbosa does not cure the deficiencies of Pomeranian because it does not disclose or suggest the combination. Moreover, Applicants point to the information submitted in the Declaration under 1.132 which shows that the claimed combination of cytotoxic agent(s) and cytotoxic enhancing agent(s) resulted in a synergistic cytotoxic effect that was unexpected.
These arguments have been carefully considered, but are not found persuasive.
In response to applicant's arguments against the references individually, the Examiner recognizes that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As set forth above, Pomeranian teaches the use of selenium compounds for treating cancer and contemplates the addition of a second selenium containing compound. Barbosa et al. teach that diphenyl diselenide can retard cancer development and may be considered as a potential chemopreventitive agent. Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the pharmaceutical composition taught by Pomeranian to include diphenyl diselenide as the another selenium compound or anti-neoplastic agent/chemo-preventative agent for treatment of cancer in view of the teachings of Barbosa. The examiner has responded to the declaration above and the response is incorporated herein.
New Rejections Necessitated by Amendment:
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5, 9-13 and 17 are 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.
Regarding claim 1, claim 1 recites the limitation “precursors thereof”. However, it is unclear what precursors thereof is referring to. For example, is it a precursor of a selenite anion, a selenide anion, a selenocystine or all three? It should be noted that the specification only appears to contemplate precursors molecules that give rise to selenite anion or hydrogen selenide (see specification page 20, lines 14-18). Thus, for prior art purposes the examiner will interpret precursors to only apply to selenite anion.
Claim 9 and 10 recites the limitation "the cytotoxic agent" when referring back to the pharmaceutical composition of claim 1. However, it is unclear which cytotoxic agent of the 4 of claim 1 they are referring to. As such, there is insufficient antecedent basis for this limitation in the claim. Moreover, claim 10 also recites numerous compounds which do not appear to have antecedent basis for within claim 1. For example, selenocytamine which is not found in claim 1, nor is a pharmaceutically acceptable salt thereof.
Similarly, claim 11 and 12 recites the limitation "the one or more cytotoxicity enhancing agent" when referring back to the pharmaceutical composition of claim 1. However, it is unclear which cytotoxicity enhancing agent of the 4 of claim 1 they are referring to. For example, is it the agent that increases expression of human SLCA711 gene or an agent that activates the overexpression of NFE2L2? As such, there is insufficient antecedent basis for this limitation in the claim.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 1 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. THIS IS A NEW MATTER REJECTION.
Claim 1 has been amended to recite a pharmaceutical composition comprising one or more cytotoxic agent(s), wherein the one or more cytotoxic agent(s) are selected from a selenite anion, a selenide anion, selenocystine, precursors thereof …. Applicants contend that support for the amendment can be found throughout the application as originally filed at least on page 19, lines 14-18 and page 20, lines 14-16. A careful review of the specification and claims as originally filed, in particular, page 20, lines 14-16, does not appear to lend support for wherein the cytotoxic compound is a selenide anion or a precursor of a selenide anion or precursor of selenocystine. For example, the specification, page 20, lines 14-16, teaches “In some embodiments, the compound of category 1 is sodium selenite, potassium selenite, selenium dioxide, sodium selenide, potassium selenide, selenious acid, elemental selenium, selenite anion, any precursor molecules that give rise to selenite anion or hydrogen selenide, or a combination thereof. Thus, while the specification provides support for a selenite anion, the specification does not appear to provide support for a selenide anion or a precursor of a selenide anion or precursor of selenocystine.
Claim 1-5, 9-13 and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. THIS IS A WRITTEN DESCRIPTION REJECTION.
Claim 1 recites a pharmaceutical composition comprising one or more cytotoxic agent(s), wherein the one or more cytotoxic agents are selected from a selenite anion, a selenide anion, a selenocystine, precursors thereof, or any combination thereof;
one or more cytotoxicity enhancing agent(s), wherein the one or more cytotoxicity enhancing agent(s) are selected from a synthetic RNA encoding human SLC7A11 gene, a cystine/glutamate transporter protein encoded by human SLC7A11 gene, an agent that increases the expression of human SLC7A11 gene, an agent that increases the concentration of human cystine/glutamate transporter protein encoded by human SLC7A11 gene, an agent that activates the overexpression of NFE2L2 or ATF4 transcription factors, or any combination thereof; and one or more pharmaceutically acceptable carriers;
wherein the presence of the cytotoxicity enhancing agent increases the cytotoxicity of the composition by at least 1.5-fold compared to in the absence of the cytotoxicity enhancing agent. Thus, the claims encompass a genus of cytotoxicity enhancing agents characterized by different functional language, wherein the presence of the cytotoxicity enhancing agent increases the cytotoxicity of the composition by at least 1.5-fold compared to in the absence of the cytotoxicity enhancing agent.
The specification teaches a variety of different compounds the majority of which contain either Selenium, sulfur or tellurium and groups these into different categories 1-5, wherein categories 1 and 2 appear to encompass the cytotoxic agents of claim 1 and categories 3-5 encompass the cytotoxicity enhancing agent, although category 3 is noted as being a hybrid molecule that serves as both a cytotoxic agent and a cytoxicity enhancing agent (see for example, pages 20 to page 48). For the category 4 and 5 compounds, the specification teaches that one common characteristics of this class of molecules, with certain exceptions, is that these molecules alter the redox potential of the microenvironment of cancer or normal cells or blood at a systemic level by effluxing endogenous thiols in human normal and cancer cells, wherein similar properties are exhibited by some of the category 3 molecules as well, since these contain one of the building blocks or functional groups that is implicated in the observed effects of Category 4 molecules on modulating the redox potential of the microenvironment of cancer or normal cells (page 26, lines 11-19). However, the specification appears to be silent on what the “one of the building blocks or functional groups” which are common and implicated in the observed effects. Moreover, the specification appears to be silent on which category is an agent that increases the expression of human SLC7A11 gene or which category is an agent that increases the concentration of human cystine/glutamate transporter protein encoded by human SLC7A11 gene or which category is an agent that activates the overexpression of NFE2L2 or ATF4 transcription factors.
Regarding the cytotoxicity enhancing agents and the claimed functional language, the specification provides a number of examples testing various compounds. For example, diphenyl selenide, tert-butyl hydroxyquinone and tunicamycin demonstrated increased expression of SLC7A11, 10 structurally diverse compounds including the three tested previously showed moderate fold changes in NRF2 and 8 structurally diverse compounds including the three tested previous showed moderate fold changes in ATF4 activity (Figures 15A, 15B, 17 and 18).
At the time the invention was filed, the state of the art appears to be silent on an agents that increases the expression of human SLC7A11 gene or agents that increases the concentration of human cystine/glutamate transporter protein encoded by human SLC7A11 gene or agents that activates the overexpression of NFE2L2 or ATF4 transcription factors (google scholar: KW: SLC7A11 or NFE2L2 or ATF4, agonist, overexpression date limit to 2020). As such, it is unclear what structures correlate with the function. Regarding at least some of the organoselenium compounds such as diphenyl diselenide, the art recognizes that there are differences in activity depending on the structure. For example, Zhang et al. (Chemical Research in Toxicology 2013; 26:456-464) found that organoselenium compounds modulate extracellular redox by induction of extracellular cysteine and cell surface thioredoxin reductase (Title). Specifically, Zhang et al. tested a number of selenium compounds:
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found that arylselenium compounds benzeneselenol (PhSeH), dibenzyl diselenide (DBDSe), diphenyl diselenide (DPDSe) and ebselen were capable of inducing extracellular cysteine accumulation via a cystin- and glucose-dependent processes but, sodium selenite, selenomethionine, seleno-l-cystine and Se-methylselenocysteine did not have these effects on macrophages under the same treatment conditions (abstract). Zhang et al. further teach that the order of effectiveness and relative magnitude of effect among the organoselenium compounds in stimulating cellular export of cysteine were DPDSe>PhSeH<ebselen>DBDSe (page 459, 2nd column, 1st full paragraph).
Thus, while the specification provides numerous compounds, the specification does not appear to be provide a structure function correlation which would allow one of skill in the art to determine which agent increases the expression of human SLC7A11 gene or which agent increases the concentration of human cystine/glutamate transporter protein encoded by human SLC7A11 gene or which agent activates the overexpression of NFE2L2 or ATF4 transcription factors.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-5, 9, 11, 13 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Chemical Research in Toxicology 2013; 26:456-464).
Zang et al. found that organoselenium compounds modulate extracellular redox by induction of extracellular cysteine and cell surface thioredoxin reductase (Title). Specifically, Zhang et al. found that arylselenium compounds benzeneselenol (PhSeH), dibenzyl diselenide (DBDSe), diphenyl diselenide (DPDSe) and ebselen were capable of inducing extracellular cysteine accumulation via a cystin- and glucose-dependent processes, wherein extracellular cysteine production was dose-dependently inhibited by glutamate, an inhibitor of cystine/glutamate antiporter (Xc- transporter) supporting the involvement of Xc- transporter for cystine uptake in the above process (abstract). Note: Xc- transporter appears to be also referred to as SLC7A11 in the art. Moreover, Zhang et al. also found that coadministration of 1.25-2.5mM sodium selenite and 2.5-5mM DPDSe synergistically inhibited cell proliferation in Hepa Iclc7 (hepatoma cells) and RAW 264.7 cells (mouse tumor induced by Abelson murine leukemia virus) and suggests that this cotreatment may extend to the combination of other organoselenium compounds with sodium selenite (page 461, 2nd column, 1st full paragraph and page 462, 2nd column 2, 2nd full paragraph).
Thus, while Zang et al. teach coadministration of sodium selenite and DPDSe, Zhang et al. do not specifically teach that the compounds together in one pharmaceutical composition.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method taught by Zhang et al. to include both agents within one pharmaceutical composition. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-combining the two agents into one composition would eliminate the need to formulate each separately and administer each separately.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Chemical Research in Toxicology 2013; 26:456-464), as applied above to claims 1-5, 9, 11, 13 and 17 above, in view of Olm et al. (PNAS 2009; 106(27): 11400-11405).
Zang et al. found that organoselenium compounds modulate extracellular redox by induction of extracellular cysteine and cell surface thioredoxin reductase (Title). Specifically, Zhang et al. found that arylselenium compounds benzeneselenol (PhSeH), dibenzyl diselenide (DBDSe), diphenyl diselenide (DPDSe) and ebselen were capable of inducing extracellular cysteine accumulation via a cystin- and glucose-dependent processes, wherein extracellular cysteine production was dose-dependently inhibited by glutamate, an inhibitor of cystine/glutamate antiporter (Xc- transporter) supporting the involvement of Xc- transporter for cystine uptake in the above process (abstract). Note: Xc- transporter appears to be also referred to as SLC7A11 in the art. Moreover, Zhang et al. also found that coadministration of 1.25-2.5mM sodium selenite and 2.5-5mM DPDSe synergistically inhibited cell proliferation in Hepa Iclc7 (hepatoma cells) and RAW 264.7 cells (mouse tumor induced by Abelson murine leukemia virus) and suggests that this cotreatment may extend to the combination of other organoselenium compounds with sodium selenite (page 461, 2nd column, 1st full paragraph and page 462, 2nd column 2, 2nd full paragraph). Zhang et al. further teach that sodium selenite cytotoxicity has been shown to be greatly enhanced with extracellular thiols via a potential mechanism in which SeO32- is reduced by thiols (page 462, 2nd column, 2nd full paragraph).
Zhang et al. does not specifically teach that the combination of selenocystine and diphenyl diselenide.
Olm et al. found that the extracellular thiol-assisted selenium uptake dependent on the Xc- cystine transporter explains the cancer-specific cytotoxicity of selenite (Title). In particular, Olm et al. teach that control experiments revealed that the redox active selenium compounds selenocystine and GSSeSG are also dependent on extracellular thiols for cytotoxicity.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to sodium selenite taught by Zhang et al. for selenocystine in view of the teachings of Olm et al. . One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
- Zhang et al. teach that sodium selenite cytotoxicity has been shown to be greatly enhanced with extracellular thiols; and
- Olm et al. teach that selenocystine and GSSeSG are also dependent on extracellular thiols for cytotoxicity.
Claim(s) 1-5, 9 and 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Nutrition Research 2015; 35: 610-617).
Wang et al. teaches synergy between sulforaphane and selenium (Sodium Selenite) in protection against oxidative damage in colonic CCD841 cells (normal colon cells) (Title and Abstract). Specifically, Wang et al. teach exposing the cells to 2.5mM sulforaphane and/or 0.1mM sodium selenite for 24 hrs (page 611, 2nd column, Section 2.3).
Thus, while Wang et al. teach coadministration of sodium selenite and sulforaphane, Wang et al. do not specifically teach that the compounds together in one pharmaceutical composition.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method taught by Wang et al. to include both agents within one pharmaceutical composition. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-combining the two agents into one composition would eliminate the need to formulate each separately and administer each separately.
Conclusion
Therefore, No claim is allowed.
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/BRANDON J FETTEROLF/Primary Examiner, Art Unit 1626