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 .
Priority
The instant application is a 371 National Stage Entry of PCT/EP2021/073283 filed on August 23, 2021 which claims priority to foreign application No. EP20193422 filed on August 28, 2020.
Status of Claims
Acknowledgement is made of amended (1-18, 21-26) and cancelled (19-20) claims filed on June 15, 2023. Claims 1-18, 21-26 are pending in instant application.
Claim Interpretation
Regarding xCT, xCT is known in the art to also be referred to as solute carrier family 7 member 11 or SLC7A11, as exemplified by Bhutia et. al.1 (see Bhutia at p. 1783 right col. ¶2). References to SLC7A11 are thus references to xCT and vice versa.
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.
Claims 1-4, 6-16, 18, 21-26 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.
Claims 1 and 22 recite “D-derivative thereof”. The specification does not specifically define “D-derivative thereof”, rather exemplified embodiments are listed:
A "D-cysteine derivative" as well as "D-derivative thereof' refers to, e.g. a non-proteinogenic amino acid derivative resulting from the formal reaction of D-cysteine at the amino group, carboxy group, or from the replacement of any hydrogen of D-cysteine by a heteroatom or to an oligomer (e.g. dimer, trimer, etc...) of one or more thereof.
Preferably, the D-cysteine derivative is selected from the group comprising D-cystine, D- homocysteine, D-meso-lanthionine, S-(2-aminovinyl)-3-methyl-D-cysteine, S-(2-aminovinyl)-D-cysteine and n-acetyl-D-cysteine or a combination of one of more thereof. Most preferably, the D-cysteine derivative is D-cystine. Salts and isomers of one or more derivatives of D-cysteine are also encompassed in the present invention. (see instant spec. at p. 10 lines 1-10)
It is unclear what compounds are encompassed or excluded from “D-derivative thereof”; are only D-enantiomers included or are L-enantiomers permitted if they perform the same function as D-cysteine? Is replacement of a hydrogen with a heteroatom referring to simple functional group substitution such as H for -NH2 or -OH? Or more complex H for -N-(any moiety) or -O-(any moiety)? Are racemic mixtures included or excluded?
Claims 2-4, 6-16, 18, 21, 23-26 fail to remedy the indefinite issue and are thus included in instant rejection.
Suggested Amendment
Examiner suggests cancelling claims 5 and 17 and amending claim 1 as follows:
A method for treating and/or preventing a cancer expressing cystine/glutamate antiporter xCT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a D-cysteine or a D-derivative thereof, or an isomer or a salt of said D-cysteine or D-derivative wherein the D-derivative is selected from the list consisting of D-cystine, D-homocysteine, D-meso-lanthionine, S-(2-aminovinyl)-3- methyl-D-cysteine, S-(2-aminovinyl)-D-cysteine and, or n-acetyl-D-cysteine.
and amending claim 22 as follows:
A method for decreasing the proliferation of a cancer cell expressing cystine/glutamate antiporter xCT, the method comprising contacting the cancer cell with a pharmaceutical composition comprising a D-cysteine or a D-derivative thereof, or an isomer or a salt of said D-cysteine or D-derivative, alone or in combination with one or more additional therapeutic agent or therapy wherein the D-derivative is selected from the list consisting of D-cystine, D-homocysteine, D-meso-lanthionine, S-(2-aminovinyl)-3- methyl-D-cysteine, S-(2-aminovinyl)-D-cysteine and, or n-acetyl-D-cysteine.
For the purposes of applying art, a D-derivative is understood to be D-cystine, D-homocysteine, D-meso-lanthionine, S-(2-aminovinyl)-3-methyl-D-cysteine, S-(2-aminovinyl)-D-cysteine and, n-acetyl-D-cysteine, or a racemic mixture thereof, or an L-enantiomer thereof with the same function.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 21 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim does not fall within at least one of the four categories of patent eligible subject matter.
The claim recites the limitation of “determining whether the cancer from the subject expresses the cystine/glutamate antiporter xCT”. This step is a judicial because it is an abstract idea insofar that it amounts to a mental process. Per MPEP § 2106.04(a)(2)(III), “The courts consider a mental process (thinking) that "can be performed in the human mind, or by a human using a pen and paper" to be an abstract idea. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1372, 99 USPQ2d 1690, 1695 (Fed. Cir. 2011). As the Federal Circuit explained, "methods which can be performed mentally, or which are the equivalent of human mental work, are unpatentable abstract ideas the ‘basic tools of scientific and technological work’ that are open to all." 654 F.3d at 1371, 99 USPQ2d at 1694 (citing Gottschalk v. Benson, 409 U.S. 63, 175 USPQ 673 (1972)).” This judicial exception is not integrated into a practical application because it amounts to nothing more than interpreting data. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no process is positively recited how the invention is to be used in the case that no such condition is identified (i.e. patients who are screened and found to have no xCT expression, there is no active step beyond mental comparison).
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.
Claims 1, 4-5, 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US Patent No. 8,227,513 B22 to Souvaniemi.
Souvaniemi claims a method of reducing cancer risk (mouth, pharynx, esophagus, stomach, intestine) by administering a food composition comprising L-cysteine, D-cysteine, cysteic acid, cysteine glycine, threo- or erythro-β-phenyl-DL-cysteine, β-tetramethylene-DL-cysteine, methionine, L-ascorbic acid, D-penicillamine, semicarbazide, reduced glutathione, β-mercaptoethylamine, D,L-homocysteine, N-acetylcysteine, L-cysteinyl-L-valine, β-β-tetramethylene-DL-cysteine, cysteinyl-glycine, mercaptoethylglycine, tre-(5)-β-phenyl-DL-cysteine, cysteine hydrochloride, or thiamine hydrochloride (see Souvaniemi at claim 1) – all considered derivatives in light of the above 35 USC 112(b), but still explicitly listing D-cysteine.
Accordingly, claims 1, 4-5, 18 are anticipated by Souvaniemi.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-8, 14, 22-26 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et. al.3
Regarding claims 1-8, 14, 22-26 and treating cancer decreasing cancer cell proliferation by administering D-derivative cystine, Liu teaches SLC7A11 has a role in protecting cells from ferroptosis and is often overexpressed in cancer cells (see Liu at p. 476 left col. ¶2). Liu also teaches the active import of cystine is toxic, forcing cancer cells expressing high SLC7A11 to risk reducing cystine to cysteine, draining NADPH, resulting in a pentose phosphate pathway dependency and under glucose starvation or GLUT inhibition ultimately leads to rapid cell death (see Liu at Abstract).
The prior art differs from the instant claims as follows: while Liu teaches cellular reprogramming by manipulating SLC7A11 and cystine conversion to kill cancer cells, Liu does not specify administering D-cysteine or a D-derivative to treat cancer.
However,
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Further regarding claims 1, 5, 22, one skilled in the art would recognize that overloading SLC7A11 by administering cystine to xCt expressing cancer cells or a subject in need thereof would increase cysteine conversion, strain NADPH, tax xCT expressing cancer cells, and suppress tumor growth by selectively killing xCT expressing cancer cells as taught and suggested by Liu (see MPEP § 2143(I)(C), (G)).
Further regarding claims 6-8 and an additional anti-cancer therapy or agent, per MPEP § 2144.06(I), "[i]t 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” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would have been obvious to combine D-cystine with an anticancer agent or therapy for treating cancer since both components would be performing their art-recognized function (treating cancer) separately or together.
Further regarding claims 3-4, 23, 26 and cancer types, since the claims are drawn to xCT expressing cancer cells and Liu teaches methods regarding xCT expressing cancer cells, the methods would be applicable to any cancer subtype so long as it expresses xCT.
Further regarding claim 24 and proliferation decrease %, it would have been obvious to one skilled in the art to optimize a method for suppressing tumor growth by improving cancer cell proliferation inhibition (see MPEP § 2144.05(II)).
Further regarding claims 2, 14 and formulating for various administration methods, it would have been obvious to one skilled in the art to identify an effective administration route and correspondingly optimize a formulation for said route, including selecting appropriate carriers, diluents, or dosages (see MPEP §§ 2144.05(II), 2143(I)(E)).
Furthermore, it is well-within the ordinary skill in the art to identify and manipulate relevant biological pathways for treatment methods.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Accordingly, claims 1-8, 14, 22-26 are obvious in view of Liu.
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Liu as applied to claims 1-8, 14, 22-26 above and in view of Belkin et. al.4
Claims 9-10 are drawn to administering D-cysteine or a D-derivative and a DAAO inhibitor such as chloropromazine to treat cancer.
The instant claims differ from the prior art as follows: While Liu teaches administering D-derivative cystine for treating cancer or inhibiting cancer cell proliferation, Liu does not teach further administering a DAAO inhibitor such as chloropromazine.
However,
Belkin teaches administering chloropromazine to stunt tumor growth (see Belkin at p. 233 middle col. ¶5).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2144.06(I), "[i]t 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” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would have been obvious to combine D-cystine and chloropromazine to treat cancer because each component would be performing the same known function (treating cancer) separate as it would together.
Furthermore, it is well-within the ordinary skill in the art to combine two cancer treatments for use in treating cancer as taught by the prior art.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Accordingly, claims 9-10 are obvious over Liu in view of Belkin.
Claims 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Liu as applied to claims 1-8, 14, 22-26 above and in view of Ausburger et. al.5 and exemplified by Hanakoa et. al.6
Claims 11-13 are drawn to administering D-cysteine or a D-derivative and an H2S-producing enzyme inhibitor such as a 3MST inhibitor such as HMPSNE.
The instant claims differ from the prior art as follows: While Liu teaches administering D-derivative cystine for treating cancer or inhibiting cancer cell proliferation, Liu does not teach further administering an H2S-producing enzyme inhibitor such as a 3MST inhibitor such as HMPSNE.
However,
Regarding claims 11-13, Ausburger teaches administering HMPSNE for treating cancer (see Ausburger at Abstract).
Further regarding claim 12, while Ausburger does not specify if HMPSNE targets a persulfurated cysteine residue located in the active site of 3MST, HMPSNE is still a known 3MST inhibitor, and still known to treat cancer. Furthermore, Hanaoka explains HMPSNE does indeed target a persulfurated cysteine residue located in the active site of 3MST (see Hanakoa at p. 5 Figure 3a-b Compound 3).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2144.06(I), "[i]t 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” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would have been obvious to combine D-cystine and HMPSNE to treat cancer because each component would be performing the same known function (treating cancer) separate as it would together.
Furthermore, it is well-within the ordinary skill in the art to combine two cancer treatments for use in treating cancer as taught by the prior art.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Accordingly, claims 11-13 are obvious over Liu in view of Ausburger as exemplified by Hanakoa.
Claims 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Liu as applied to claims 1-8, 14, 22-26 above and in view of Wang et. al.7 and Iron Disorders Institute8.
The instant claims differ from the prior art as follows: While Liu teaches administering D-derivative cystine for treating cancer or inhibiting cancer cell proliferation in a cancer expressing SLC7A11, Liu does not teach administering for a ferrotoxic or iron disease or disorder.
However,
Wang teaches SLC7A11 is upregulated during iron-overload (see Wang at p. 451 left col. ¶2).
IDI teaches iron-overload diseases include hereditary hemochromatosis (all types), African iron overload, sickle cell disease, thalassemia, X-linked sideroblastic anemia, enzyme deficiencies (pyruvate kinase; glucose-6-phosphate dehydrogenase) and very rare protein transport disorders aceruloplasminemia and atransferrinemia (see IDI at p. 2).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(D), a prima facie case of obviousness exists for applying a known technique to a known method or product ready for improvement to yield predictable results. It would have been obvious to one of ordinary skill to apply the teachings of Liu (administer D-cystine) to iron-overload disorders taught by IDI because Liu and Wang both teach an overlapping underlying pathology feature of cancer and iron-overload disorders: overexpression of SLC7A11.
Furthermore, it is well-within the ordinary skill in the art to identify relevant pathways and pathology features when treating a disease.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Accordingly, claims 15-17 are obvious over Liu in view of Wang and IDI.
Conclusion
Claims 1-18, 21-26 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SOPHIA J REILLY whose telephone number is (703)756-5669. The examiner can normally be reached 9:00 am - 5:00 pm EST M-F.
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/S.R./Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
1 Bhutia et. al. "Amino acid transporters in cancer and their relevance to “glutamine addiction”: novel targets for the design of a new class of anticancer drugs." Cancer Res. 2015, 75, 1782-1788. DOI: 10.1158/0008-5472.CAN-14-3745. Hereinafter Bhutia.
2 Filed Nov 19, 2009, patented July 24, 2012. Hereinafter Souvaniemi.
3 Liu et. al. "Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer" Nature Cell Biology 2020, 22, 476–486. Published March 30, 2020. Hereinafter Liu.
4 Belkin et. al. "Effect of Reserpine and Chlorpromazine on Sarcoma 37" Science, 1957, 125, 3241, 233-234. DOI: 10.1126/science.125.3241.233
5 Augsburger et. al. "Role of 3-Mercaptopyruvate Sulfurtransferase in the Regulation of Proliferation, Migration, and Bioenergetics in Murine Colon Cancer Cells" Biomolecules. 2020, 10, 3, 447, 1-20. DOI: 10.3390/biom10030447 Published March 13, 2020. Cite No. CE in the IDS filed 2/23/23. Hereinafter Ausburger.
6 Hanakoa et. al. "Discovery and Mechanistic Characterization of Selective Inhibitors of H2S-producing Enzyme: 3-Mercaptopyruvate Sulfurtransferase (3MST) Targeting Active-site Cysteine Persulfide" Scientific Reports, 2017, 7, 40227, 1-12. DOI: 10.1038/srep40227. Hereinafter Hanakoa.
7 Wang et. al. "Characterization of ferroptosis in murine models of hemochromatosis" Hepatology 2017, 66, 2, 449-465. DOI: 10.1002/hep.29117. Hereinafter Wang.
8 Iron Disorders Institute. "Iron Overload" Wayback Machine Web Archive December 4, 2019. Hereinafter IDI.