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
Applicant’s amendment filed on 15 December 2025 and 20 January 2026 has been entered. Claims 23-24, 26-27, 29-30, and 34-35 are amended, and claim 28 is canceled. Claims 18-27, 29-32, and 34-35 are pending. Claims 18-22 and 31-32 are withdrawn. Claims 23-27, 29-30 and 34-35 are under examination.
Claim Objections
Claims 23-24, 26, and 29-30 are objected to because of the following informalities:
Claim 23 recites, in lines 1-2, a convoluted method preamble, which can be amended to: A method for treating cancer in a subject undergoing an initial chemotherapy, comprising: …
Claim 23 recites, in line 3, an ungrammatical limitation “obtaining from the subject undergoing the initial chemotherapy a sample from the cancer disease”, which can be amended as “obtaining a sample of the cancer from the subject undergoing an initial chemotherapy”. Similarly, claims 26 and 30 recite “a sample from the cancer of the subject”, which can be amended as “a sample of the cancer from the subject”.
In claim 23, the comma before the “and” at the end of line 13 needs to be changed to a semi colon.
In claim 24, the commas terminating the wherein clauses on lines 5, 6, and 8 need to be changed to semi colons.
Claim 29 should add the indefinite article “a” before the word “genome” on line 2.
Claim 30 should change the “an” before “SAMHD1 inhibitor” in combinations (ii) and (iii), and the last wherein clause to “a”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
(Modified to address claim amendment) Claims 26-27, 29-30, and 34-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of treating acute myeloid leukemia (AML), glioma, glioblastoma, and urothelial carcinoma cancers by administering a combination of a SAMHD1 inhibitor and either an oncolytic herpes simplex virus 1 (HSV-1) or nucleoside analog selected from cytarabine, decitabine, fludarabine, clofarabine, or nelarabine, does not reasonably provide enablement for a method of treating any cancer other than acute myeloid leukemia, glioma, glioblastoma, and urothelial carcinoma cancers with a combination of a SAMHD1 inhibitor and either any oncolytic virus other than herpes simplex virus 1 or any nucleoside analog other than cytarabine, decitabine, fludarabine, clofarabine, or nelarabine. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As stated in the MPEP §2164.01(a) “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”.”
In re Wands, 8 USPQ2d 1400 (1988), provided factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112 (a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. They are:
The nature of the invention
The state of the prior art
The predictability or lack thereof in the art
The amount of direction or guidance present
The presence or absence of working examples
The breadth of the claims
The quantity of experimentation needed, and
The level of skill in the art
It is noted that all of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
The breadth of the claims: claims 26 and 30 are drawn to a method of treating a cancer in a subject, wherein the cancer disease is glioma, glioblastoma, urothelial carcinoma, or acute myeloid leukemia. Claim 27, which is dependent on independent claim 26, recites that the cancer disease is “an initial solid cancer and/or a recurrent solid cancer”. The broadest reasonable interpretation of the term “solid cancer” is any cancer disease that forms abnormal solid masses of tissue. This claim term encompasses a large genus of cancer diseases, so encompasses a method of treating any solid cancer disease known in the art. Claims 24 and 26-27 all recite a step of administering any nucleoside analog (NA) together with an inhibitor of SAMHD1 and/or CTPS, or any oncolytic virus together with an inhibitor of SAMHD1 and/or CTPS. Claim 25 recites a Markush group of NA that limits the NA used to didanosine, vidarabine, BCX4430, cytarabine, emtricitabine, lamivudine, zalcitabine, abacavir, aciclovir, entecavir, stavudine, telbivudine, zidovudine, idoxuridine, nelarabine, fludarabine, or trifluridine, and also limits the oncolytic virus to be oncolytic HSV. Claim 34 limits the SAMHD1 inhibitor of claim 26 to molecules miRNA 181a/b, anti-SAMHD1 inhibitor antibod[ies], and T-cell receptor[s]. Claim 35 limits the SAMHD1 inhibitory proteins of claim 26 to Vpx or Vpr, and claim 29 further limits the Vpx and Vpr to being those encoded by particular viruses.
The presence and absence of working examples and the amount of direction or guidance provided: the instant disclosure provides some working examples demonstrating that chemotherapy resistance to nucleoside analog or oncolytic virus treatments can be overcome by administering SAMHD1 inhibitors in combination with nucleoside analogs (namely cytarabine, decitabine, fludarabine, nelarabine, clofarabine, gemcitabine, cladribine, thioguanine, ribavirin, and daunorubicin as shown in FIG. 9), or herpes simplex virus 1 (HSV-1) (specification Examples 4, 6-7, 9, and 11). These examples were administered to acute myeloid leukemia (AML) cell lines (examples 4, 6, and 9), glioma/glioblastoma cells (example 7), and urothelial carcinoma cells were also used (example 11).
However, there are no additional working examples, nor additional guidance present in the instant disclosure that provides a reasonable rationale for one of ordinary skill in the art to use the results of the working examples provided in the instant disclosure to formulate a method to treat any type of cancer other than acute myeloid leukemia, glioma, glioblastoma, and urothelial carcinoma cancers with a combination of a SAMHD1 inhibitor and either any oncolytic virus other than herpes simplex virus 1 or any nucleoside analog other than cytarabine, decitabine, fludarabine, clofarabine, or nelarabine.
The state of the prior art and level of predictability in the art: the prior art recognized that specific nucleoside analogs are appropriate to treat specific cancer diseases, and that just because one nucleoside analog was appropriate for one type of cancer, does not necessarily mean that that same analog would be useful for treating a different cancer disease. Galmarini et al. (Nucleoside analogues and nucleobases in cancer treatment, Lancet Oncol 2002; 3: 415–24) provides a list of some common nucleoside analogs and the particular types of cancer diseases that those analogs are used to treat (Galmarini Table 1). Thus, given the state of the art as established by Galmarini, one of ordinary skill in the art would not predict, for example, cytarabine to be useful for treating pancreatic cancer, but instead would find it predictable that gemcitabine would be useful for the treatment. As such, one of ordinary skill in the art would understand that specific nucleoside analogs must be applied in the treatment of specific cancer diseases, and so it would be unpredictable to apply any type of nucleoside analog in a treatment of any type of cancer disease.
Further confounding the issue of predictability, the instant disclosure demonstrates in working example 6, that only cytarabine, decitabine, fludarabine, clofarabine, or nelarabine showed a significant, positive, correlative effect in combination with SAMHD1 inhibition on the IC50 of the respective nucleoside analogs in two different AML cell lines (drawings Fig. 9). All of the other nucleoside analogs tested did not produce a significant positive effect, thus one of ordinary skill in the art would conclude that the underperforming nucleoside analogs in Fig. 9 would not be predictably useful for treating AML cancer disease, let alone any type of cancer disease, in a method comprising administering a combination of any NA and a SAMHD1 inhibitor.
The prior art also recognized that SAMHD1 inhibition on its own was not predictably relevant for treating cancer. In fact, Schott et al. (SAMHD1 in cancer: curse or cure?, Journal of Molecular Medicine (2022) 100:351–372) provides a series of circumstances where SAMHD1 mutations (including inhibitions) were actually widely prevalent in a variety of different cancers (Schott FIG. 2). In one circumstance, somatic mutation of SAMHD1 was identified to be a potential driving event to the development of chronic lymphocytic leukemia (CLL) (Schott Pg. 353 para. 2 sentence 3). Schott also stated that SAMHD1 mutations might actually contribute to CLL treatment resistance in vivo, which is the opposite effect of what is claimed in the instant invention (Schott Pg. 353 para. 2 sentence 7). Thus, one of ordinary skill in the art would not recognize SAMHD1 inhibition could be used to treat any cancer disease.
The quantity of experimentation needed: one of ordinary skill in the art would be required to circumvent a widely unpredictable art using the little, and sometimes contradictory, guidance from the instant disclosure and the prior art. One of ordinary skill in the art would thus be subjected to undue experimentation to use the invention commensurate in scope with the instant claims.
In conclusion, one of ordinary skill in the art would find a method of treating any cancer other than acute myeloid leukemia, glioma, glioblastoma, and urothelial carcinoma cancers with a combination of a SAMHD1 inhibitor and either any oncolytic virus other than herpes simplex virus 1 or any nucleoside analog other than cytarabine, decitabine, fludarabine, clofarabine, or nelarabine, to be unpredictable, and would thus be subjected to undue experimentation to use the invention commensurate in scope with the instant claims.
(Modified to address claim amendment) Claims 24, 26-27, 30, and 34 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.
Claims 24 and 30 recite the broad genus of SAMHD1 inhibitors of SAMHD1 inhibitory nucleic acids, inhibitory small molecules, SAMHD1 inhibitory proteins, and a molecule that acts as a negative regulator of SAMHD1 expression.
Claims 26-27 recite the broad genus of SAMHD1 inhibitors. Without any limitation on the scope of SAMHD1 inhibitors, the genus is interpreted to include any inhibitor of SAMHD1.
Claim 34 limits the SAMHD1 inhibitor of claim 26 to a miRNA 181a/b molecule, an inhibitory anti-SAMHD1 antibody, or an inhibitory T-cell receptor.
The specification lacks sufficient written description for the full genus of SAMHD1 inhibitors as recited, including the subgenera of SAMHD1 inhibitory nucleic acids, small molecules, proteins, negative regulators, antibodies, and T cell receptors.
MPEP §2163.02 states “[a]n applicant shows that the inventor was in possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the inventor was in possession of the claimed invention.”
The instant specification only describes the following species of SAMHD1 inhibitors: viral proteins Vpx and Vpr (specification pg. 22 Example 4, Figs. 6 and 19 ), miRNAs 181a and 181b (specification pg. 22 Example 5 , Fig. 7 ), and a SAMHD1 inhibiting short hairpin RNA (shRNA) expressed by transcription of lentiviral vector plasmid pLK0.1-puro-SAMHD1-shRNA (specification pgs. 20-21 Example 2 , Fig. 4). The specification does not describe any specific SAMHD1 inhibiting antibodies, T-cell receptors (TCRs), or other SAMHD1 inhibitors.
The prior art discloses the same and some additional SAMHD1 inhibitors. Ballana et al. (SAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction, Trends in Microbiology, November 2015, Vol. 23, No. 11) discloses SAMHD1 inhibitors Vpx (Ballana Abstract and Fig. 1) and cyclin-dependent kinases CDK2 and CDK6 (Ballana pg. 685 para. 1 , Fig. 2). Jin et al. (MicroRNA-181 expression regulates specific post-transcriptional level of SAMHD1 expression in vitro, Biochemical and Biophysical Research Communications 452 (2014) 760–767) discloses SAMHD1 inhibitor miRNAs 181a and 181b levels (Jin Abstract). Seamon et al. (Small Molecule Inhibition of SAMHD1 dNTPase by Tetramer Destabilization, J. Am. Chem. Soc. 2014, 136, 9822-9825) discloses SAMHD1 inhibitor pppCH2dU, a 5’ methylene dUTP (Seamon Abstract). The prior art lacks any other disclosure or description of the broad genus of claimed SAMHD1 inhibitors.
Lacking sufficient prior art knowledge of the structure-function relationship for the claimed genus of SAMHD1 inhibitors, the specification does not provide sufficient description of SAMHD1 inhibitors such that one of ordinary skill in the art would be able to reasonably predict the entire genus of claimed SAMHD1 inhibitors. Thus, one of ordinary skill in the art would conclude that Applicant was not in possession of the entire genus of SAMHD1 inhibitors as claimed.
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 29 and 35 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.
Claim 29 recites the viral protein Vpr is encoded by SIVmus and SIVdeb. The term “encoded by” indicates that the claimed proteins are encoded by specific DNA gene sequences, or transcribed RNA sequences of an expressed gene. Thus, the limitations following the term “encoded by” would be expected to be DNA or RNA sequences. However, the claim recites that the Vpr proteins are encoded by viruses, not DNA or RNA. Viruses are submicroscopic infectious agents that replicate inside living host cells. While they do have nucleic acid genomes, viruses themselves are not equivalent to DNA or RNA sequences. Thus, it is incorrect to state that a protein is encoded by a virus; rather, it would be correct to state that a protein is produced by a virus. It is unclear how the Vpr proteins can be encoded by the viruses themselves, rather than the DNA or RNA sequences from which the Vpr proteins are synthesized through genetic transcription and translation.
(New necessitated by amendment) Claim 35 recites wherein SAMHD1 inhibitory proteins of the SAMHD1 inhibitor comprise Vpx or Vpr. There is insufficient antecedent basis for the limitation “SAMHD1 inhibitory proteins” in the claim. Claim 29 is dependent on claim 35, so is indefinite for the same reason.
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.
(Maintained) Claim 27 is rejected 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.
Claim 27 recites that the cancer disease of claim 26 is “an initial solid cancer, and/or a recurrent solid cancer”. However, claim 26 recites that the cancer disease is “glioma, glioblastoma, urothelial carcinoma, or acute myeloid leukemia”. The scope of the “solid cancer” limitation of claim 27 includes any solid cancer, including solid cancers other than glioma, glioblastoma, urothelial carcinoma, or acute myeloid leukemia. The genus of cancers in claim 27 is broader that the genus of cancers in parent claim 26, thus claim 27 fails to further limit parent claim 26.
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.
(Maintained) Claims 23, 24, 26, 27, 29, 30 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Lancaster et al. (US 20150080249 A1, published March 2015) in view of Momparler et al. (Enhancement of Anti-Neoplastic Activity of Cytosine Arabinoside Against Human HL-60 Myeloid Leukemic Cells by 3-Deazauridine, Int. J. Cancer: 49,573-576 (1991)) in view of Ballana et al. (SAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction, Trends in Microbiology, November 2015, Vol. 23, No. 11), and as evidenced by Faruqi et al. (Cytarabine. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-: https://www.ncbi.nlm.nih.gov/books/NBK557680).
Lancaster teaches a method of predicting the sensitivity of cancer cells to a chemotherapy comprising assaying the expression level of SAMHD1 in a sample of cancer cells and comparing them with a control (Lancaster claim 7 and Table 3). Lancaster also teaches that high sensitivity scores are indicative of cells sensitive to chemotherapy, and low sensitivity scores are indicative of chemoresistance (Lancaster claim 7).
However, Lancaster does not teach terminating and replacing a chemotherapy treatment of a chemotherapy-resistant cancer with a combination treatment comprising administering either an NA together with an inhibitor of SAMHD1 and/or CTPS, or alternatively an oncolytic virus together with an inhibitor of SAMHD1 and/or CTPS, nor that their method can be used to determine the chemotherapy sensitivity of glioma, glioblastoma, urothelial carcinoma, or acute myeloid leukemia (AML) cancers.
Momparler teaches the use of the inhibitory molecule 3-deazauridine (3-DU) in combination with nucleoside analog cytarabine (AraC or cytosine arabinoside) to treat HL-60 acute myeloid leukemia cells (Momparler Abstract). Momparler also teaches that drug resistance is a major reason for failure of cytarabine (AraC) chemotherapy of acute myeloid leukemia, and that the combination of cytarabine with 3-DU as taught therein could overcome the drug resistance (Momparler Abstract). 3-DU was known to be an inhibitor of CTP synthetase (CTPS) (Momparler Intro. Para. 3 sentence 2), the enzyme responsible for the synthesis of cytarabine’s competitor, cytidine. Momparler teaches that the combination of 3-DU and cytarabine produces a synergistic cytotoxic effect on HL-60 AML cells (Momparler Discussion para. 1 sentences 3-4), and can be used to circumvent drug resistance in cytarabine mediated chemotherapy of leukemia (Momparler Abstract).
Momparler taught that 3-DU inhibits CTP synthetase (CTPS), the enzyme responsible for the synthesis of cytarabine’s competitor, cytidine. Thus, one of ordinary skill in the art would understand that administration of 3-DU would reduce the intracellular levels of cytarabine’s competitor, cytidine, thereby increasing the incorporation of cytarabine into DNA.
However, Momparler does not teach the use of a SAMHD1 inhibitor.
Ballana teaches that SAMHD1 is a triphosphohydrolase enzyme that controls intracellular levels of deoxyribonucleoside triphosphates (dNTPs) by cleaving excess dNTPs (Ballana Abstract sentence 1), and that inhibition of SAMHD1 leads to an overall increase in the intracellular concentration of dNTPs (Ballana Fig. 1B). Ballana also teaches that lentiviral protein Vpx produced by HIV-2 degrades SAMHD1, thus Vpx is an inhibitor of SAMHD1 (Ballana Abstract sentence 2). Although Ballana is primarily focused on viral infections, one of ordinary skill in the art would understand that the increase in the intracellular concentration of dNTPs caused by inhibiting SAMHD1 in hyperproliferative viral cells would also be reasonably expected to occur in hyperproliferative cancer cells because Ballana teaches that the nucleotide regulatory effect of SAMHD1 is relevant to cancer diseases (Ballana Pg. 687 para. 2 sentence 1).
Cytarabine is a cytidine analog that competes with cytidine for incorporation into DNA, and incorporation of the dNTP form of cytarabine (Ara-dCTP) into DNA inhibits rotation of the molecule within the DNA, thereby ceasing DNA replication and ultimately leading to cellular apoptosis, as evidenced by Faruqi (Faruqi Bridging para of pages 1-2 titled “Mechanism of Action”). Therefore, one of ordinary skill in the art would reasonably and predictably conclude that inhibiting SAMHD1 would increase the intracellular concentration of cytarabine’s dNTP form, Ara-dCTP, which is then incorporated into the DNA of a hyperproliferative cell, leading to the inhibition of DNA replication, and ultimately leading to an increase cellular apoptosis in rapidly dividing cells, such as the cancer cells of AML.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to have determined the sensitivity of an AML cancer to a chemotherapy using the method of Lancaster, and then replace a chemoresistant cancer treatment with a new treatment comprising a combination of SAMHD1 inhibitor Vpx taught by Ballana, and nucleoside analog cytarabine and CTPS inhibitor 3-DU as taught by Momparler.
One of ordinary skill in the art would have been motivated to assess if an AML cancer is sensitive or resistant to cytarabine chemotherapy using the method of Lancaster because doing so allow one of ordinary skill in the art to advantageously adjust an AML chemotherapy treatment strategy if a subject’s AML cancer is determined to be resistant to cytarabine.
One of ordinary skill in the art would have had reasonable expectations of success because Momparler taught that drug resistance is a major reason for failure of cytarabine (AraC) chemotherapy of AML, and Lancaster teaches a method of determining the drug resistance of cancer cells to a chemotherapy. Thus, one of ordinary skill in the art would reasonably expect that Lancaster’s method can be used to determine if an AML cancer is resistant to cytarabine, which would then allow them to adjust their treatment strategy accordingly.
One of ordinary skill in the art would have been motivated to replace a cytarabine resistant chemotherapy treatment of AML cancer with a new treatment using a combination of nucleoside analog cytarabine, CTPS inhibitor 3-DU, and SAMHD1 inhibitor Vpx into a single treatment of AML because doing so would enhance the chemotherapeutic effect of cytarabine in the chemoresistant AML cancer cells, thereby overcoming the cytarabine resistance. One of ordinary skill in the art would have had reasonable expectations of success because Momparler teaches that 3-DU reduces the intracellular concentration of cytarabine’s competitor, cytidine, by inhibiting CTPS, and Ballana teaches that inhibiting SAMHD1 increases the concentrations of dNTPs, such as the dNTP form of cytarabine (Ara-dCTP). Thus, the combined effect of increasing the concentration of the dNTP form of therapeutic agent cytarabine, and reducing the concentration of cytarabine’s competitor cytidine, the combination of cytarabine, 3-DU, and Vpx into a new treatment would be reasonably expected by one of ordinary skill in the art to enhance the chemotherapeutic effect of cytarabine in AML cancer cells, including AML cancer cells that were previously determined to be resistant to cytarabine chemotherapy using Lancaster’s method.
(Maintained) Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Lancaster in view of Momparler and Ballana as applied to claims 23-27, 29-30 and 35 above, and further in view of Jin et al. (MicroRNA-181 expression regulates specific post-transcriptional level of SAMHD1 expression in vitro, Biochemical and Biophysical Research Communications 452 (2014) 760–767).
Lancaster, Momparler, and Ballana do not teach a SAMHD1 inhibitory miRNA 181a/b, antibody, or T-cell receptor (TCR).
Jin teaches miRNA 181 levels were negatively correlated with SAMHD1 expression levels, and that miRNA 181 acted directly on the SAMHD1 3’ UTR and regulated SAMHD1 mRNA levels after transcription (Jin Abstract). Jin teaches that over-expression of miRNA 181 significantly reduced the level of SAMHD1 expression in acute myeloid leukemia (AML) THP-1 cells (Jin Abstract).
MPEP §2144.06(II) states “[i]n order to rely on equivalence as a rationale supporting an obviousness rejection, the equivalency must be recognized in the prior art, and cannot be based on applicant’s disclosure or the mere fact that the components at issue are functional or mechanical equivalents. In re Ruff, 256 F.2d 590, 118 USPQ 340 (CCPA 1958)” and “[a]n express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)”.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to have substituted the SAMHD1 inhibitor, miRNA 181a/b, as taught by Jin, for the SAMHD1 inhibitor, Vpx protein, in the method of Lancaster, Momparler, and Ballana above. One of ordinary skill in the art would have been motivated to do so because Vpx and miRNA 181a/b were both known in the art to inhibit SAMHD1, and thus would have been art recognized equivalents of each other suitable for the same purpose of inhibiting SAMHD1.
Response to Arguments
Applicant's arguments filed 15 December 2025 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments that they have amended the claims to limit the treated cancers to acute myeloid leukemia, glioma, glioblastoma, or urothelial carcinoma cancers, the oncolytic virus to herpes simplex virus 1, and the nucleoside analogs to cytarabine, decitabine, fludarabine, clofarabine, or nelarabine; thereby obviating the rejection (Remarks pg. 9 last para.), although amended claims 24 and 30 now require the treated cancers to glioma, glioblastoma, urothelial carcinoma, and acute myeloid leukemia cancers, the oncolytic virus to herpes simplex virus 1, and the nucleoside analogs to cytarabine, decitabine, fludarabine, clofarabine, or nelarabine; claims 25-27, 29, and 34-35 are still not enabled. Claim 25 still recites several nucleoside analogues other than cytarabine, decitabine, fludarabine, clofarabine, or nelarabine. Claims 26-27, 29, and 34-35 do not recite any limitation that limits the oncolytic virus to herpes simplex virus 1, and the nucleoside analogs to cytarabine, decitabine, fludarabine, clofarabine, or nelarabine.
Regarding Applicant’s arguments that they have amended claims 24 and 30 to limit the SAMHD1 inhibitor to a SAMHD1 inhibitory nucleic acid, an inhibitory small molecule, SAMHD1 inhibitory proteins, or a molecule that acts as a negative regulator of SAMHD1 expression, thereby obviating the rejection (Remarks pg. 10 para. 4), the new limitation “the [SAMHD1] inhibitor is selected from the group consisting of: a SAMHD1 inhibitory nucleic acid, an inhibitory small molecule, SAMHD1 inhibitory proteins, or a molecule that acts as a negative regulator of SAMHD1 expression” in claims 24 and 30 was previously recited in now canceled claim 28, which was included in the written description rejection. As previously described, the genus of SAMHD1 inhibitors that fall within the subgenera of SAMHD1 inhibitory nucleic acids, inhibitory small molecules, SAMHD1 inhibitory proteins, and molecules that act as a negative regulators of SAMHD1 expression still lacks sufficient written description that adequately describes a representative number of species within the genus of SAMHD1 inhibitors. Additionally, no amendment that addresses this issue was made in independent claim 26.
Regarding Applicant’s arguments that the MPEP does not require that the specification provide working examples for every single embodiment within a claimed genus, that the specification provides a representative number of working examples for each major subgenus recited in the claims along with guidance describing how these diverse molecular classes achieve SAMHD1 inhibition through different mechanisms; and that the specification provides extensive guidance regarding the structure-function relationships and mechanisms by which SAMHD1 inhibitors operate (Remarks pgs. 10-11 bridging para.), the rejection did not state nor require that the specification provide working examples for every single embodiment within a claimed genus. The specification describes only 5 working examples, 3 of which fall within the scope of inhibitory nucleic acid (miRNAs 181a and 181b, and a shRNA), and 2 which fall within SAMHD1 inhibitory proteins (Vpx and Vpr). The specification lacks any working examples or guidance for inhibitory small molecules or molecules that act as negative regulators of SAMHD1 expression. Applicant has not provided any references as to where in the specification the extensive guidance regarding the structure-function relationships and mechanisms by which SAMHD1 inhibitors operate is located. The materials and methods disclosed on pgs. 16-20 of the specification do not provide any method which can be used to establish a structure-function relationship that can be reasonably extended to the entire claimed genus of SAMHD1 inhibitors. Example 2 uses shRNA to deplete SAMHD1, example 4 uses Vpx and Vpr to inhibit SAMHD1, and example 5 uses miRNAs 181a and 181b to inhibit SAMHD1. None of these examples describe or assess the structure-function relationship or the inhibitory mechanisms of the described inhibitors, nor is there any description or guidance that demonstrates that the shRNA, Vpx and Vpr inhibitory proteins, and miRNAs 181a and 181b SAMHD1 inhibitory examples can adequately describe the entire claimed genus of SAMHD1 inhibitors.
Regarding Applicant’s arguments that since claim 27 depends on claim 26, the limitations of claim 26 should be read into claim 27, and thus claim 27 requires that the cancer is glioma, glioblastoma, urothelial carcinoma, or acute myeloid leukemia and is an initial solid cancer and/or a recurrent solid cancer (Remarks pg. 11 para. 4), the scope of the “solid cancers” limitation in claim 27 is broad enough to include any initial or recurrent solid cancer, which encompasses a broader array of cancers compared to claim 26’s glioma, glioblastoma, urothelial carcinoma, or acute myeloid leukemia cancers. Claim 27 does not recite that the cancer of claim 26 is further characterized as an initial solid cancer and/or a recurrent solid cancer. Rather, the claim recites that the cancer is an initial solid cancer and/or a recurrent solid cancer, which reads as though the cancer is any initial solid cancer and/or a recurrent solid cancer.If Applicant intends for the cancer to be a glioma, glioblastoma, urothelial carcinoma, or acute myeloid leukemia cancer and an initial solid cancer and/or a recurrent solid cancer, claim 27 needs to be amended to directly indicate that the cancer of claim 26 is further characterized as an initial solid cancer and/or a recurrent solid cancer, or that the glioma, glioblastoma, urothelial carcinoma, or acute myeloid leukemia cancer is an initial solid cancer and/or a recurrent solid cancer.
Regarding Applicant’s arguments that reference Lancaster is misinterpreted because Lancaster requires the measurement of a panel of at least ten genes, not SAMHD1 alone, and does not teach assaying SAMHD1 expression alone as a biomarker for predicting chemotherapy sensitivity (Remarks pg. 12 para. 4 through pgs. 12-13 bridging para.), the instant claims are not limited to measuring just SAMHD1 alone. The claims recite "determining a level of SAMHD1 in the sample from the subject"; there is no limitation which requires no other analyte be measured. Lancaster teaches the claimed active step of assaying the level of SAMHD1 in Lancaster's claim 7 and Table 3. Regardless, even though Lancaster's claim 7 states assaying the expression levels of ten or more genes listed in Table 3, Lancaster does not recite a limitation that the expression levels of each of those at least ten genes must be measured together in one assay. The BRI of Lancaster includes assaying the level of SAMHD1 in its own separate assay (thus alone).
Regarding Applicant’s arguments that Lancaster is directed to gene analysis for ovarian cancer, and does not provide any teaching or suggestion that SAMHD1 measurement would be relevant for the specific cancer types recited in the present claims (Remarks pg. 13 para. 1), Lancaster teaches a method of assessing sensitivity of a cancer to chemotherapeutics comprising assaying the levels of SAMHD1 expression, thus Lancaster teaches that SAMHD1 measurement is relevant to cancer. Lancaster’s focus on ovarian cancer is still relevant to the instant invention because Lancaster’s method assays the sensitivity of a cancer to chemotherapeutics. As for the specific cancer types present in the claims, the rejection is not based on Lancaster alone. Momparler teaches that drug resistance is a major reason for cytarabine chemotherapy failure, and also teaches treating AML cancers using nucleoside analogue cytarabine. Ballana teaches that inhibiting SAMHD1 leads to an increase in dNTPs, such as the dNTP form of cytarabine, within cells, and also teaches that viral protein Vpx is a potent SAMHD1 inhibitor. When Momparler and Ballana are combined, one of ordinary skill in the art would reasonably recognize that SAMDH1 inhibition leads to an increase in available cytotoxic cytarabine in the method of treating AML cancer disclosed by Momparler. Consequently, this also means that the lack of SAMHD1 inhibition (high SAMHD1 levels) would decrease the availability of cytotoxic cytarabine in a chemotherapy treatment of AML cancer, making the cytarabine chemotherapy less effective. Thus, when Lancaster, Momparler, and Ballana are considered together it becomes evident to one of ordinary skill in the art that SAMHD1 levels are very relevant to the success of some chemotherapy treatments, so one of ordinary skill in the art would recognize that performing Lancaster’s method of assessing the sensitivity of a cancer to chemotherapeutics by assaying SAMHD1 expression levels would give a reasonable assessment as to how sensitive a cancer disease is to chemotherapy.
Regarding Applicant’s arguments that Momparler does not teach the claimed combination of a SAMHD1 inhibitor with a nucleoside analog, and that Momparler does not teach or suggest that 3-DU inhibits SAMHD1 (Remarks pg. 13 para. 5), the rejection was not based on Momparler alone. Momparler teaches 3-DU reduces the intracellular concentration of cytarabine’s competitor, cytidine, by inhibiting CTPS, and Ballana teaches that SAMHD1 inhibition leads to an overall increase in the intracellular concentration of dNTPs. Ballana also teaches an effective SAMHD1 inhibitor Vpx. When Momparler and Ballana are combined, it would have been obvious that the combined effect of increasing concentration of dNTP form of therapeutic NA cytarabine though SAMHD1 inhibition with Vpx, together with reducing the concentration of cytarabine’s competitor cytidine through CTPS inhibition with 3-DU, would be reasonably expected to enhance the chemotherapeutic effect of cytarabine in AML cancer cells. Momparler teaches that 3-DU inhibits CTPS, not SAMHD1. The rejection never stated that 3-DU inhibits SAMHD1.
Regarding Applicant’s arguments that Bellana does not disclose that the effect of SAMHD1 inhibition on viral cells can be applied to cancer cells and is entirely directed to viral cells, not cancer cells (Remarks pg. 13-14 bridging para. through pg. 14 para. 3), the rejection was not based on Ballana alone. Momparler teaches an AML cancer treatment using nucleoside analog cytarabine. Ballana teaches that inhibiting SAMHD1 leads to an increase in dNTPs, such as the dNTP form of cytarabine, within cells, and also teaches that viral protein Vpx is a potent SAMHD1 inhibitor. Although Ballana’s Fig. 1B may not use cancer cells, the figure does clearly demonstrate that the increase in dNTPs within cells is a consequence of SAMDH1 inhibition itself, and nowhere in Ballana’s disclosure limits this effect to only being in the viral cells taught therein. Rather, Ballana’s statement that defects in nucleoside metabolism can be seen in cancer suggests that cancer cells are also susceptible to deregulation of the dNTP pool used in DNA synthesis (Ballana pg. 687 para. 2). Thus, when Momparler and Ballana are combined, one of ordinary skill in the art would reasonably recognize that SAMDH1 inhibition would lead to an increase in available cytotoxic cytarabine in the method of treating AML cancer disclosed by Momparler.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Alexander M Duryee/Examiner, Art Unit 1657
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657