DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-11 are pending. Examiner previously required a restriction (dated March 6, 2026). In response, Applicant elected, without traverse, Group I which encompasses claims 1-10. Accordingly, claim 11 is withdrawn.
Status of Priority
The present application is a continuation-in-part of PCT/KR2022/009183, filed on June 28, 2022 which claims priority to the Korean Patent Application No. 10-2021-0083887, filed on June 28, 2021.
Election/Restrictions
As a reminder, Applicant elected, without traverse, Group I which encompasses claims 1-10. Examiner also required Applicant to elect a species for each of the following:
one specific compound (with structure and name provided) or a pharmaceutically acceptable salt thereof for inhibiting expression of a glutaminase (GLS) gene,
one specific compound (with structure and name provided) or a pharmaceutically acceptable salt thereof for inhibiting a function of a protein expressed by glutaminase (GLS) gene
one specific agent (with structure and name provided) or a pharmaceutically acceptable salt thereof for inhibiting the expression of a gene selected from the group consisting of a Phosphoglycerate Dehydrogenase (PHGDH) gene, a Serine hydroxymethyltransferase (SHMT) gene, and a Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 2 or MethenyltetrahydrofolateCyclohydrolase (MTHFD2) gene, and
one specific agent (with structure and name provided) or a pharmaceutically acceptable salt thereof for inhibiting a function of a protein expressed by a gene selected from the group consisting of a PHGDH gene, an SHMT gene, and an MTHFD2.
Accordingly, Applicant elected the following species, without traverse:
The species elected for point A AND B is:
the CB839 compound:
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The species elected for point C AND D is:
the NCT503 compound:
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Applicant states that claims 1-10 read on the elected species. The elected species was found in the prior art as discussed in sections “Claim Rejections - 35 USC § 102” and “Claim Rejections - 35 USC § 103” below.
Specification - Abstract
The abstract of the disclosure is objected to as explained below:
Currently the abstract recites:
If PHGDH, SHMT and MTHFD2 inhibitors are co-administered to patients with cancer in which the expression level of a glutaminase (GLS) gene or a protein encoded thereby has increased, 1C metabolism is more effectively inhibited such that there is a synergistic effect on the inhibition of cancer cell proliferation in patients with refractory cancer that is difficult to treat because of recurrence, metastasis, and anticancer drug resistance, thereby enabling cancer to be very effectively treated.
As presently written, the statement appears to indicate that a PHGDH inhibitor, an SHMT inhibitor and an MTHFD2 inhibitor (i.e., all three inhibitors) are co-administered together to a patient exhibiting elevated GLS gene expression or elevated levels of the protein encoded by the GLS gene.
However, the statement does not clearly indicate that the invention involves one of the following options (as described by the specification and the claim set):
a pharmaceutical composition comprising (i) an inhibitor of GLS gene expression and (ii) an inhibitor of PHGDH or SHMT or MTHFD2 gene expression to a patient with cancer or
a pharmaceutical composition comprising (i) an inhibitor of the function of a protein expressed by the GLS gene and (ii) an inhibitor of the function of a protein expressed by the PHGDH or SHMT or MTHFD2 gene to a patient with cancer.
Please correct the abstract appropriately to ensure consistency with the invention as described in the specification and claims.
Specification - Disclosure
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1, 6, and 7 are objected to because of the following informalities:
Claim 1:
To avoid 112 issues and for clarity and consistency, claim 1 should read:
“A pharmaceutical composition for treatment of gastric cancer comprising:
a compound or a pharmaceutically acceptable salt thereof for inhibiting expression of a glutaminase (GLS) gene; and
an agent or a pharmaceutically acceptable salt thereof for inhibiting the expression of a gene selected from the group consisting of a Phosphoglycerate Dehydrogenase (PHGDH) gene, a Serine hydroxymethyltransferase (SHMT) gene, and a Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 2 or MethenyltetrahydrofolateCyclohydrolase (MTHFD2) gene .”
Claim 6:
To avoid 112 issues and for clarity and consistency, claim 6 should read:
“A pharmaceutical composition for treatment of gastric cancer comprising:
a compound or a pharmaceutically acceptable salt thereof for inhibiting a function of a protein expressed by glutaminase (GLS) gene; and
an agent or a pharmaceutically acceptable salt thereof for inhibiting a function of a protein expressed by a gene selected from the group consisting of a PHGDH gene, an SHMT gene, and an MTHFD2 gene.”
Claim 7:
To be consistent with the instant specification and claim set, claim 7 should read:
“… wherein the compound or the agent is…”
However, please confirm if this is what Applicant intended claim 7 to be interpreted.
Appropriate correction is required.
Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the claim set.
Claim Rejections - 35 USC § 112(a)
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.
Scope of Enablement
Claims 1-10 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:
A pharmaceutical composition for treatment of gastric cancer comprising:
a compound or a pharmaceutically acceptable salt thereof for inhibiting expression of a glutaminase (GLS) gene; and
an agent or a pharmaceutically acceptable salt thereof for inhibiting the expression of a gene selected from the group consisting of a Phosphoglycerate Dehydrogenase (PHGDH) gene, a Serine hydroxymethyltransferase (SHMT) gene, and a Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 2 or MethenyltetrahydrofolateCyclohydrolase (MTHFD2) gene
wherein the compound or agent specifically binds to the mRNA of the gene and is a shRNA;
The pharmaceutical composition of point (A), further comprising an anticancer agent;
The pharmaceutical composition of point (A), wherein the cancer is an epithelial mesenchymal transition (EMT) subtype;
A pharmaceutical composition for treatment of gastric cancer comprising:
a compound or a pharmaceutically acceptable salt thereof for inhibiting a function of a protein expressed by glutaminase (GLS) gene; and
an agent or a pharmaceutically acceptable salt thereof for inhibiting a function of a protein expressed by a gene selected from the group consisting of a PHGDH gene, an SHMT gene, and an MTHFD2;
wherein the compound is a compound represented by Chemical Formula 1 or 2 and wherein the agent is a compound represented by Chemical formula 3, 4, or 5;
The pharmaceutical composition of point (D), further comprising an anticancer agent;
The pharmaceutical composition of point (D), wherein the cancer is an epithelial mesenchymal transition (EMT) subtype;
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and 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 evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed to make and use the invention based on the content of the disclosure, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims a pharmaceutical composition for the prevention or treatment of cancer comprising:
a compound or a pharmaceutically acceptable salt thereof for inhibiting expression of a glutaminase (GLS) gene (or inhibiting a function of a protein expressed by glutaminase [GLS] gene); and
an agent or a pharmaceutically acceptable salt thereof for inhibiting the expression of a gene (or inhibiting a function of a protein expressed by a gene) wherein the gene is selected from the group consisting of a Phosphoglycerate Dehydrogenase (PHGDH) gene, a Serine hydroxymethyltransferase (SHMT) gene, and a Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 2 or MethenyltetrahydrofolateCyclohydrolase (MTHFD2) gene.
State of the prior art
References cited:
Polet et al. (Polet) (Polet, F. et al. Reducing the serine availability complements the inhibition of the glutamine metabolism to block leukemia cell growth. Oncotarget 2015, 7, 1765-1776.)
Jacque et al. (Jacque) (Jacque, N. et al. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood 2015, 126, 1346-1356.)
Jin et al. (Jin) (Jin, H. et al. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer. eLife 2020, 9, e56749.)
Gross et al. (Gross) (Gross, M. I. et al. Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer. Mol Cancer Ther 2014, 13, 890-901.)
At the time of filing, methods for inhibiting gene expression, including the use of shRNA, were well known in the art (see Polet and Jacque as described in “Rejection Part 1” of “Claim Rejections - 35 USC § 103”; Polet describes PHGDH gene expression inhibition and Jacque describes GLS1 gene expression inhibition).
Likewise, small-molecule inhibitors capable of inhibiting the activity of specific proteins were known and routinely employed in cancer research (see Jin as described in “Claim Rejections - 35 USC § 102”; Jin discloses a composition comprising CB-839 and NCT-503).
However, the prior art is highly unpredictable with respect to cancer treatment. Different cancers are often driven by distinct pathways, and the therapeutic effectiveness of inhibiting a particular gene or protein frequently depends on whether that target plays a significant role in the development or progression of the specific cancer being treated. For example, Gross teaches that “CB-839, a potent and selective inhibitor of glutaminase… exhibited in vitro antiproliferative activity against a panel of TNBC cell lines, but not estrogen receptor (ER) or HER2+ cell lines” (pg. 891, left col., last paragraph, 1st and 2nd sentences). Thus, the prior art demonstrates that even within a single cancer type (i.e., breast cancer), different subtypes may exhibit markedly different responses to inhibition of the same target.
Additionally, the prior art does not provide a generally applicable structure-function relationship that would permit a POSITA to reliably predict which compounds or agents would successfully inhibit the expression of the recited genes or inhibit the function of the recited proteins and, in turn, provide effective prevention or treatment across the broad range of cancers encompassed by the claims.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry, medical biology, and/or a related field and would be familiar with:
standard methods for evaluating therapeutic efficacy of compounds as well as
standard methods for gene silencing and assessing the biological effects of gene knockdown.
The breadth of the claims
The claims are broad insofar as the instant claims recite a pharmaceutical composition that can comprise of any compound or any agent of any structure (so long as they have the function recited in claims 1 or 6) for the prevention or the treatment of any cancer.
The presence or absence of working examples
The instant specification provides a limited number of working examples. The experimental data primarily involve treatment of gastric cancer cells with one or more compounds represented by Chemical Formulas 1-5. Furthermore, only Example 7 expressly discloses a pharmaceutical composition comprising both CB-839 and NCT-503. This single composition represents a narrow embodiment relative to the broad scope of the claims. Moreover, the working examples are directed to treatment-related endpoints and do not provide experimental evidence demonstrating prevention of cancer.
The amount of direction or guidance present and the quantity of experimentation needed to make and use the invention based on the content of the disclosure
The amount of direction and guidance provided in the specification is limited relative to the breadth of the claimed subject matter. The claims encompass a pharmaceutical composition that can comprise of any compound or any agent of any structure (so long as they have the function recited in claims 1 or 6) for the prevention or the treatment of any cancer. However, the instant specification provides only limited examples involving a small number of specific compounds, primarily compounds represented by Chemical Formulas 1-5.
The instant specification provides little guidance for identifying additional compounds or agents that fall within the scope of the claims. In particular, the claims are not limited to any common structural class, sequence, or other identifying characteristic that would permit a POSITA to readily determine which compounds or agents possess the recited functional properties. Instead, the claims encompass potentially vast numbers of structurally unrelated small molecules, antibodies, aptamers, antisense oligonucleotides, siRNAs, shRNAs, miRNAs, or other agents capable of affecting the recited gene expression or protein function.
Moreover, the prior art demonstrates that inhibition of a claimed target does not necessarily correlate with therapeutic efficacy. For example, Jin teaches that “a significant number of liver cancer cell lines are glutamine dependent but fail to respond to CB-839” (pg. 4, section “A compounds screen identifies that ASCT-2 inhibitor V-9302 sensitizes GD [glutamine dependent] liver cancer cells to CB-839 treatment”, 1st sentence). Specifically, Jin reports that CB-839 severely impaired proliferation in only a subset of glutamine-dependent liver cancer cell lines, while other glutamine-dependent cell lines exhibited little response to treatment (pg. 4, 1st paragraph, 5th to last sentence). Thus, the prior art demonstrates that even where a cancer is dependent upon the GLS pathway and a compound is known to successfully inhibit GLS activity (i.e., CB-839), therapeutic efficacy cannot be reliably predicted. Accordingly, a POSITA would be required to perform substantial additional experimentation to determine which PHGDH inhibitors, SHMT inhibitors, or MTHFD2 inhibitors are therapeutically effective for which cancers when combined with which GLS inhibitors. Identifying these inhibitors involve either testing inhibitors known in the art, are designing new inhibitors (which further require undue experimentation to determine which combination of substituents on which specific core, in which specific substitution pattern of a small molecule inhibitor would result in the desired therapeutic effect). The instant specification provides insufficient guidance for making such determinations across the full scope of the claimed subject matter.
Furthermore, the claims encompass prevention of cancer in addition to treatment. The specification provides no working examples and little guidance regarding the prevention of cancer. Unlike treatment studies, which may evaluate the response of existing cancer cells or tumors, prevention studies require demonstrating that cancer development is avoided in subjects that have not yet developed the disease. Such studies generally require extended observation periods, and the specification provides insufficient guidance regarding how prevention should be evaluated across the broad range of cancers encompassed by the claims.
Accordingly, the specification does not provide guidance commensurate with the breadth of the claims, and a POSITA would be required to engage in extensive and undue experimentation to identify operative compounds and agents throughout the full scope of the claims and to establish their effectiveness for preventing or treating the numerous cancers encompassed in the instant claim set.
Claims 2-5, which are dependent on claim 1, and claims 7-10, which are dependent on claim 6, are also rejected for further requiring and/or reciting elements that are outside the scope of the enabling elements listed above.
Written Description
Claims 1-10 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.
According to MPEP § 2163:
“Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’ See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
“An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described.").”
In the instant case, the claims are exceedingly broad and are directed to a pharmaceutical composition that can comprise any compound or any agent of any structure (so long as they have the function recited in claims 1 or 6) for the prevention or the treatment of any cancer.
The language of the instant claims is similar to the language of a claimed method directed to “selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product” (See Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004); this statement is reproduced above and can be found in MPEP § 2163).
The instant application does provide specific examples of inhibitors encompassed by the claims (i.e., compounds of instant Chemical Formulas 1-5) (note: in Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004), there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2). However, the five small molecular compounds explicitly disclosed for use in treating gastric cancer does not adequately reflect the structural diversity of the claimed genus which encompasses a pharmaceutical composition that can comprise of any compound or any agent of any structure (so long as they have the function recited in claims 1 or 6; this includes a vast number of structurally unrelated small molecules, antibodies, aptamers, antisense oligonucleotides, siRNAs, shRNAs, or miRNAs) for the prevention or the treatment of any cancer.
Therefore, claims 1 and 6 fail to comply with the written description requirement.
Claims 2-5 (which are dependent on claim 1) and claims 7-10 (which are dependent on claim 6) are also rejected for further requiring and/or reciting elements that do not have written description support as discussed above.
Claim Rejections - 35 USC § 112(d)
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.
Claims 2, 4, 5, 9, and 10 are 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.
According to MPEP § 2114, section II:
“‘[A]pparatus claims cover what a device is, not what a device does.’ Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1469, 15 USPQ2d 1525, 1528 (Fed. Cir. 1990) (emphasis in original). A claim containing a ‘recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus’ if the prior art apparatus teaches all the structural limitations of the claim.”
This can also be translated to a composition claim. A composition claim covers what a composition is, not what a composition does. Therefore, a claim containing a recitation with respect to the manner in which a claimed composition is intended to be employed does not differentiate the claimed composition from a prior art composition (or, in this case, from another instantly claimed composition) if the prior art composition (or the other instantly claimed composition) teaches all the structural limitations of the claim. In other words, claims directed to a pharmaceutical compositon but only refer to the type of cancer or the manner in which the composition works or performs, is not a limitataion of the composition.
Therefore, claims 2, 4, and 5 do not further limit the scope of the claim it is dependent upon and are substantial duplicates of claim 1. Claims 9 and 10 also do not further limit the scope of the claim it is dependent upon and are substantial duplicates of claim 6.
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.
Note on 35 USC § 102 and § 103 Rejections
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.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 4-7, 9, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Jin et al. (Jin) (Jin, H. et al. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer. eLife 2020, 9, e56749.)
Jin discloses that treatment of SNU398 and HepG2 cell lines (used to study liver cancer) with a combination of CB-839 and NCT503 produced a moderate synergistic inhibitory effect on cell viability (see Figure 3d). Thus, Jin teaches a composition comprising CB-839 and NCT503 and further demonstrates anticancer activity of the composition in liver cancer cell models.
Recall: in response to the election requirement, Applicant elected a pharmaceutical composition comprising CB839 and NCT503. Applicant also stated that:
CB-839 is species A and B (i.e., a compound that can both inhibit the expression of a GLS gene and inhibit a function of a protein expressed by the GLS gene) and that
NCT503 is species C and D (i.e., an agent that can both inhibit the expression of a gene selected from the group consisting of a PHGDH gene, a SHMT gene, and an MTHFD2 gene and inhibit a function of a protein expressed by one of the three genes listed above.
Jin explicitly discloses the same composition comprising CB-839 and NCT503. Since claims 1, 2, 4-7, 9, and 10 are directed a pharmaceutical composition, and Applicant has identified CB-839 and NCT503 as species encompassed by those claims, Jin discloses the elected composition recited in the instant application. Therefore, claims 1, 2, 4-7, 9, and 10 are anticipated by Jin.
With respect to claims 1, 2, 4-7, 9, and 10 reciting prevention or treatment of cancer, the specific form of the compound or agent, the cancer being an EMT subtype, or the cancer being any of the specific cancer types recited in claims 5 and 10, such language does not distinguish the claimed composition (i.e., CB-839 + NCT503) from the identical composition disclosed by Jin.
As discussed above in “Claim Rejections - 35 USC § 112d,” a composition claim covers what a composition is, not what a composition does. Therefore, a claim containing a recitation with respect to the manner in which a claimed composition is intended to be employed does not differentiate the claimed composition from a prior art composition if the prior art composition teaches all the structural limitations of the claim.
Additionally, MPEP § 2112, section I recites:
“"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable.”
Therefore, claims 1, 2, 4-7, 9, and 10, which encompass a pharmaceutical composition comprising CB-839 and NCT503, are anticipated by Jin which discloses the same composition.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over the references as described below:
Rejection Part 1:
Polet et al. (Polet) (Polet, F. et al. Reducing the serine availability complements the inhibition of the glutamine metabolism to block leukemia cell growth. Oncotarget 2015, 7, 1765-1776.)
Jacque et al. (Jacque) (Jacque, N. et al. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood 2015, 126, 1346-1356.).
Polet discloses that silencing the PHGDH gene expression through shRNA-mediated knockdown in combination with CB-839 decreases the growth of HL-60 leukemia cells (see Figure 6c and Figure 6 caption). Thus, Polet teaches that simultaneous inhibition of the glutaminase pathway and the PHGDH pathway suppresses leukemia-cell proliferation.
Polet does not disclose antileukemia activity resulting from inhibition of GLS gene expression. Jacque is relied upon for this disclosure.
Jacque discloses that “[b]oth knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34+ progenitors” (abstract). In other words, Jacque teaches that inhibiting GLS1 gene expression and pharmacologic inhibition of GLS1 with CB-839 are two approaches for suppressing leukemic cell growth.
Therefore, one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the claimed invention to substitute the CB-839 compound employed by Polet with a GLS-directed shRNA as taught by Jacque. A POSITA would be motivated to make this modification since Jacque demonstrates that inhibiting GLS1 gene expression and pharmacologic inhibition of GLS1 with CB-839 can both suppress leukemic cell growth. A POSITA would, therefore, had a reasonable expectation that replacement of CB-839 with a GLS gene-expression inhibitor (to yield a pharmaceutical composition comprising a GLS gene-expression inhibitor and a PHGDH gene-expression inhibitor) would likewise inhibit leukemia cell proliferation.
As such, claims 1, 2, 4, and 5 are rendered obvious.
Rejection Part 2:
Polet et al. (Polet) (Polet, F. et al. Reducing the serine availability complements the inhibition of the glutamine metabolism to block leukemia cell growth. Oncotarget 2015, 7, 1765-1776.)
Jeong et al. (Jeong) (Jeong, S. et al. High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells. Cell Metabolism 2021, 33, 145-159.).
Polet discloses that silencing the PHGDH gene expression through shRNA-mediated knockdown in combination with CB-839 decreases the growth of HL-60 leukemia cells (see Figure 6c and Figure 6 caption). Thus, Polet teaches that simultaneous inhibition of the glutaminase pathway and the PHGDH pathway suppresses leukemia-cell proliferation.
Polet does not disclose antileukemic activity resulting from inhibition of the PHGDH protein that is encoded by the PHGDH gene. Jeong is relied upon for this disclosure.
Jeong discloses that “[c]onsistent with the PHGDH-knockdown in vivo model, NCT-503 treatment led to substantially lower engraftment of hCD45+ cells in bone marrow” (pg. 154, right col., paragraph right before the Discussion section, 3rd sentence). In other words, Jeong discloses that NCT-503 (a compound that inhibits the function of the PHGDH protein) produced the same type of biological outcome that was observed when the PHGDH gene expression was inhibited by genetically knocking down the gene.
Therefore, one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the claimed invention to substitute the PHGDH-directed shRNA as taught by Polet with NCT503 as taught by Jeong. A POSITA would be motivated to make this modification since Jeong demonstrates that inhibiting PHGDH gene expression and inhibition of the PHGDH inhibitor with NCT-503 can both suppress leukemic cell growth. A POSITA would, therefore, had a reasonable expectation that replacement of PHGDH-directed shRNA with a PHGDH protein inhibitor such as NCT-503 (to yield a pharmaceutical composition comprising CB-839 and NCT-503) would likewise inhibit leukemic-cell proliferation.
As such, claims 6, 7, 9, and 10 are rendered obvious.
Rejection Part 3:
Jin et al. (Jin) (Jin, H. et al. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer. eLife 2020, 9, e56749.)
Wei et al. (Wei) (Wei, L. et al. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nature Communications 2019, 10, 4681.).
The teachings of Jin as they apply to claims 1, 2, 4-7, 9, and 10 are as discussed in the “Claim Rejections - 35 USC § 102” section above and incorporated herein.
Jin does not disclose NCT-503 working synergistically with another anticancer agent (besides CB-839). Wei is relied upon for this disclosure.
Wei teaches that “treatment of PHGDH inhibitor NCT-503 works synergistically with Sorafenib to abolish HCC [hepatocellular carcinoma] growth in vivo” (abstract). Wei further teaches that “[s]orafenib is the standard treatment for advanced hepatocellular carcinoma (HCC)” (abstract). Therefore, Wei teaches the use of NCT503 in combination with an anticancer agent for the treatment of liver cancer.
Therefore, one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the claimed invention to modify the liver-cancer treatment composition disclosed by Jin (i.e., the composition elected by Applicant which comprises CB-839 + NCT503) by further incorporating sorafenib as taught by Wei. A POSITA would have been motivated to make this modification because Wei demonstrates that NCT503 and sorafenib work synergistically to suppress HCC growth. In view of Wei’s teaching, a POSITA would have reasonably expected that addition of sorafenib to the CB-839/NCT-503 combination disclosed by Jin would provide an effective liver-cancer treatment regimen and could further enhance suppression of HCC growth (recall that in Jin, the CB-839 + NCT503 composition has moderate synergy so adding sorafenib could enhance suppression of liver cancer cells).
As such, claims 3 and 8 are rendered obvious.
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
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