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 .
Claims 1-35 are pending.
Election/Restrictions
Applicant’s elections without traverse of the following in the reply filed on 18 June 2026 is acknowledged:
Invention Group IV (Claims 11, 13-25, and 31-25, drawn to a method comprising depleting/degrading/inhibiting PIP4K2C protein in one or more cells of a subject),
The species that is modified/degraded/inhibited/depleted/deleted is protein,
Species of inhibitor: a degrader (Remarks p. 8 ¶0) wherein the degrader is a small molecule that specifically binds to PIP4K2C protein, and
Species for examination purposes: method is performed in vivo.
Claims 1-10, 12, and 26-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 18 June 2026.
Claims 13-19 depend from Claim 12 which recites deleting/degrading/mutating a genomic site and therefore isn’t part of Invention Group IV. However, the claims are examined because they are interpreted to depend from Claim 11 because, e.g., an antibody (Claim 16) does not delete/degrade/mutate a genomic site.
Claim 20 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 18 June 2026.
The claims are examined to the extent they read on the elected invention and species.
Claims 11, 13-19, 21-25, and 31-35 are examined.
Information Disclosure Statement
The IDS(es) has been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because:
Figs. 1AB: It is not clear what the “Immunogenicity” scale is or what it’s supposed to show.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See p. 39 ¶0. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Note about Citations to Page and Paragraph Number
The following style is used for citations to page and paragraph number (for documents that don’t have ¶ #s): p. # refers to PDF p. #. ¶#1 refers to the first complete ¶ on a page. ¶0 refers to a partial ¶ that is the first ¶ on a page.
Claim Objections
Claims 11, 13-14, 18-19, and 25 are objected to because of the following informalities:
Claim 11 should spell out and define PIP4K2C on first use: Phosphatidylinositol-5-Phosphate 4-Kinase Type 2 Gamma (PIP4K2C).
Claims 13-14 should depend from Claim 11. See also §112b and §112d.
Claim 14 will be better if it’s reworded to recite: …wherein degrading PIP4K2C comprises contacting the PIP4K2C with a binding moiety, wherein the binding moiety is directly or indirectly linked to an agent that signals cells to degrade the PIP4K2C bound to the agent.
Claims 18 and 19 should then recite:
…wherein “indirectly linked” means that interaction between the binding moiety and the agent occurs before the PIP4K2C is contacted with the binding moiety (Claim 18) and
…wherein “indirectly” linked means that interaction between the binding moiety and the agent occurs after the PIP4K2C is contacted with the binding moiety (Claim 19).
Claim 25 should recite …binds with specificity to a PIP4K2C epitope having a sequence with…. Claim 25 should be consistent in hyphenating (or not) 5-AA and 30-AA.
Appropriate correction is required.
Claim Interpretation
Claim 11 recites a method comprising depleting, degrading, or inhibiting PIP4K2C in one or more cells of a subject. As discussed in the Requirement for Restriction/Election of Species mailed 18 March 2026 and below in §112b, the claims are not clear about what PIP4K2C is being depleted/degraded/inhibited—the gene Pip4k2c/pip4k2c or the protein Pip4k2c/PIP4K2C. Note that this confusion occurs because the claims and the Spec. inconsistently use each term to refer to either the gene, the protein, or both. In the Requirement for Restriction/Election of Species, Applicant was asked to clarify their usage but they did not. In the interest of compact prosecution, unless a claim has a recitation that explicitly indicates otherwise (i.e., Claim 12 recites modifying a genomic site), the claims are interpreted as referring to Pip4k2c/PIP4K2C protein. The claims are interpreted that way because Applicant elected Invention Group IV which is directed to inhibitors of PIP4K2C protein and because PIP4K2C is capitalized.
In the interest of compact prosecution, Claims 13-14 are interpreted to depend from Claim 11 instead of Claim 12 (so Claims 15-19 are also interpreted to ultimately depend from Claim 11). See also §112b and §112d.
Claims 14-15, 17-19 recite the agent. Those claims depend from Claim 14 which recites an agent that signals cells to degrade the PIP4K2C bound to the agent. The agent refers to the agent that signals cells to degrade the PIP4K2C.
Claims 14, 16-19, and 23-25 recite a binding moiety or the binding moiety. The claim doesn’t recite that the binding moiety binds PIP4K2C, so it encompasses a huge number of binding moieties. In the interest of compact prosecution, for purpose of applying art, a binding moiety is interpreted to encompass any moiety that binds PIP4K2C.
Claim 16 is interpreted as meaning the small molecule binds specifically to the PIP4K2C.
Claim Rejections - 35 USC § 112a
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.
Claims 11, 13-19, 21-25, and 31-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description (WD) rejection.
Claim 11 recites a method comprising depleting, degrading, or inhibiting PIP4K2C in one or more cells of a subject. As discussed in §Claim interpretation, the claims are interpreted as being drawn to inhibiting PIP4K2C protein because PIP4K2C is capitalized in the claim (i.e., Pip4k2c) and because Applicant elected Invention Group IV.
Broad claim 11 encompasses the large genus of depleting/degrading/inhibiting PIP4K2C protein. Any kind of technique or compound that depletes/degrades/inhibits PIP4K2C protein would be encompassed by the claims as instantly presented. There is a WD problem because the claims and Spec. do not disclose what technique or compound is responsible for the depletion/degradation/inhibition of PIP4K2C protein.
Claim 13 recites the degrading PIP4K2C comprises contacting PIP4K2C with a degrader compound.
That broad claim encompasses the large genus of compounds that can be used to degrade PIP4K2C. There is a WD problem because the claim encompasses a genus of compounds defined solely by their function of degrading PIP4K2C protein but does not disclose any structure responsible for that function.
Claim 14 recites the degrading PIP4K2C comprises contacting a binding moiety with PIP4K2C wherein the binding moiety is directly or indirectly linked to an agent that signals cells to degrade the PIP4K2C bound to the agent. Claim 15 recites that the agent that signals cells to degrade the PIP4K2C is an E3 ubiquitin ligase.
Broad Claim 14 encompasses the large genus of compounds that comprise a binding moiety that can make contact with PIP4K2C. Note that the claim doesn’t recite that the binding moiety binds PIP4K2C, so the claim is broad to a point of meaninglessness. What biomolecule cannot contact PIP4K2c? The broad claims encompass the large genera of compounds that are agents that can signal to cells to degrade PIP4K2C bound to the agent and that are E3 ubiquitin ligases. There is a WD problem because the claims encompass broad genera of compounds defined solely by their function of being binding moieties that can make contact with PIP4K2C, agents that can signal to a cell to degrade PIP4K2C bound to the agent, and agents that are E3 ubiquitin ligases but the Spec. does not disclose any structures responsible for those functions.
Claim 16 recites that the binding moiety is a small molecule. Claim 21 recites inhibiting the PIP4K2C comprises inhibiting function of PIP4K2C. Claim 22 recites the inhibiting comprises administering an inhibitor of PIP4K2C. Claim 23 recites that inhibiting the function comprises administering a binding moiety or small molecule inhibitor of the PIP4K2C. Claim 24 recites that the binding moiety binds with specificity to the PIP4K2C protein and Claim 25 recites that the binding moiety binds with specificity to an epitope having a sequence with at least 95% sequence identity to a 5- to 30-AA portion of SEQ ID NO 1. Those broad claims encompass the huge genera of binding moieties that are small molecules and specifically bind PIP4K2C (Claim 16), compounds that inhibit the function of PIP4K2C (Claim 21), inhibitors of PIP4K2C (Claim 22), binding moieties that inhibit PIP4K2C or small molecules that inhibit PIP4K2C (Claim 23), binding moieties that bind with specificity to PIP4K2C (Claim 24), and binding moieties that bind with specificity to an epitope having a sequence with at least 95% sequence identity to a 5- to 30-AA portion of SEQ ID NO 1. There is a WD problem because the claims encompass broad genera of compounds defined solely by their functions (i.e., specifically binding PIP4K2C, inhibiting PIP4K2C, binding with specificity to PIP4K2C, and binding with specificity to an epitope having a sequence with at least 95% sequence identity to a 5- to 30-AA portion of SEQ ID NO 1) but the Spec. does not disclose any structures responsible for those functions.
Regarding Claim 25, there is a WD problem because the claim recites the binding moiety binds with specificity to an epitope having a sequence with at least 95% sequence identity to a portion of SEQ ID NO 1 that is anywhere from at least 5 to at least 30 AAs. The recitation that the binding moiety binds with specificity to an epitope having a sequence with at least 95% sequence identity to a portion of SEQ ID NO 1 that is anywhere from at least 5 to at least 30 AAs encompasses a huge number of proteins, so it also encompasses a huge number of binding moieties that would bind to those proteins. Again, the claim encompasses a huge number of binding moieties defined solely by their function of specifically binding a protein epitope that comprises a small segment of the sequence of SEQ ID NO 1 but the Spec. doesn’t disclose the structure of any binding moieties that bind to an epitope comprising any at least 5-AA sequence, let alone a representative number of species of such binding moieties, let alone a representative number of species of all that the claim encompasses.
Claim 17 recites that the binding moiety is indirectly linked to the agent via hydrogen bonding, hydrophobic interaction, steric interaction, hydrophilic interaction, or a combination thereof.
That broad claim encompasses the broad genera of linkages between the binding moiety and the agent that comprise hydrogen bonding, hydrophobic interaction, steric interaction, hydrophilic interaction, or a combination thereof. There is a WD problem because the claim encompasses forms of linkage but nothing in the claims or Spec. disclose what structure(s) is responsible for forming the linkage or what conditions allow linkage.
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
The Spec. describes (p. 4 ¶2-3) that their method includes compositions and methods for inhibiting or degrading PIP4K2C, but those descriptions are inadequate to provide WD support because they don’t provide any details about what physical structures are common to agents that inhibit or degrade PIP4K2C. The Spec. describes (starts on p. 15 ¶2) binding agents that can be used to deliver Pip4k2c modifying agents to cells and/or to inhibit Pip4k2c function and (starts on p. 28 ¶2) degradation of PIP4K2C proteins including by linking a degradation signal (including an E3 ubiquitin ligase) to the PIP4K2C protein. The Spec.’s entire substantive discussion of small molecules that bind PIP4K2C proteins is one sentence on p. 29 (¶4) referring to two WO documents. Those descriptions are inadequate to provide WD support for all that is claimed because they don’t provide any details about what physical structures are common to agents bind to or inhibit PIP4K2C. Those § merely describe what is possible but no details are provided that would indicate that Applicant was in possession of a representative number of species from the broad genera of PIP4K2C inhibitors/binding moieties/etc. claimed, including from each of the other genera and subgenera discussed above. Regarding the E3 ubiquitin ligases, Wikipedia (“Ubiquitin ligase”. 2026. Accessed on 22 July 2026) teaches (§Ubiquitin ligase families) there are 500-1000 E3 ligases. The Spec. hasn’t disclosed which of those are or are not appropriate to use in the claimed invention or how to determine which are or aren’t appropriate to use.
Regarding Claim 17, nothing in the Spec. provides any details about what structures may be used to indirectly link that binding moiety to the agent via hydrogen bonding or hydrophobic/steric/hydrophilic interaction.
Regarding what structure(s) is encompassed by the various binding moieties, small molecules, inhibitors of PIP4K2C or PIP4K2C function, binding moieties that bind with specificity to an epitope having 95% identity to a segment of SEQ ID NO 1 or structures that may be used to indirectly link that binding moiety to the agent via hydrogen bonding or hydrophobic/steric/hydrophilic interaction, the Spec. does not provide information describing its features. The Spec. does not disclose what physical structure(s) is responsible for the claimed function(s).
Applicant’s examples (start on p. 51 ¶5) show only experiments wherein a Pip4k2c gene is inhibited or knocked out. None of the examples shows or discusses any kind of inhibitor that inhibits or induces degradation of PIP4K2C protein. Therefore, those examples are not sufficient to provide written description support for the broad genera encompassed by the claims. Although the claims claim the functional characteristics (i.e., compounds or methods that deplete/degrade/inhibit PIP4K2C, binding moieties that may contact PIP4K2C, agents and E3 ubiquitin ligases that signal a cell to degrade PIP4K2C, small molecules that specifically bind to PIP4K2C, binding moieties that bind with specificity to an epitope having 95% identity to a segment of SEQ ID NO 1, structures that may be used to indirectly link that binding moiety to the agent via hydrogen bonding or hydrophobic/steric/hydrophilic interaction), the functional characteristic(s) is not coupled with any known structure.
Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for performing the claimed function(s) of depleting/degrading/inhibiting PIP4K2C, contacting or binding PIP4K2C, signaling a cell to degrade PIP4K2C, specifically binding to PIP4K2C, specifically binding to an epitope having 95% identity to a segment of SEQ ID NO 1, indirectly linking the binding moiety to the agent via hydrogen bonding or hydrophobic/steric/hydrophilic interaction. The Spec. does not disclose any core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for depleting/degrading/inhibiting PIP4K2C, contacting or binding PIP4K2C, signaling a cell to degrade PIP4K2C, specifically binding to PIP4K2C, specifically binding to an epitope having 95% identity to a segment of SEQ ID NO 1, indirectly linking the binding moiety to the agent via hydrogen bonding or hydrophobic/steric/hydrophilic interaction in such a way to demonstrate possession of the full invention as claimed at time of filing. The Examples are all directed to genetic modification that removes or inhibits a pip4k2c gene—not a PIP4K2C protein—and even those methods of genetic modification do not share a core structure.
The Spec. does not support the breadth of what is claimed. Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genera and subgenera that are encompassed by the claims.
While none of these elements is specifically required to demonstrate possession, in combination their absence means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of the full breadth of the invention claimed. Claims 11, 13-19, and 21-25 are rejected for failing to demonstrate possession of the claimed invention. Claims 13-19, 21-25, and 31-35 are rejected because they depend from Claim(s) 11, 13-19, and/or 21-25 and do not remedy the issues.
Claims 33-35 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:
Claim 11: an in vitro or ex vivo method of inhibiting Phosphatidylinositol-5-Phosphate 4-Kinase Type 2 Gamma (PIP4K2C), the method comprising administering an inhibitor of PIP4K2C protein, wherein the inhibitor of PIP4K2C protein is either NIH-12848 or a131;
Claim 14: The method of Claim 11, wherein degrading PIP4K2C comprises contacting a cell comprising the PIP4K2C with a compound that comprises a binding moiety that is directly or indirectly linked to cereblon, wherein the binding moiety is either NIH-12848 or a131;
Claim 33a: An in vitro or ex vivo method of treating cancer in an organoid or in cells of a subject by administering to the organoid or cells an inhibitor of PIP4K2C protein, wherein the inhibitor of PIP4K2C protein is either NIH-12848 or a131, and wherein the cells are not B-cells, T-cells, or natural killer cells;
Claim 33b: A method of treating cancer in a subject by administering to the subject an inhibitor of PIP4K2C protein, wherein the inhibitor of PIP4K2C protein is a131, and wherein the cancer is not a cancer of B-cells, T-cells, or natural killer cells; and
Claims 34-35: The method of Claim 33b, wherein administering the inhibitor of PIP4K2C protein reduces tumor size by at least 20% vs. control,
does not reasonably provide enablement for the full scope of the claims as written. 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. This is a scope of enablement rejection.
The factors to be considered in determining whether a disclosure would require undue experimentation include: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the specification; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and the nature of the invention: With respect to claim breadth, the standard under 35 U.S.C. §112(a) entails determining what the claims recite and what the claims mean as a whole.
Methods of Claims 11, 13-19, 21-25, and 31-35 have been interpreted as methods of treatment because they depend from Claim 11 which recites a method comprising depleting, degrading, or inhibiting PIP4K2C in one or more cells of a subject. That indicates that the cells could be inside a subject. Claims 33-35 recite administering the PIP4K2C inhibitor to a subject who has or is suspected of having cancer, immune deficiency, autoimmune disease, infection or a combination thereof (Claim 33), that the method reduces the onset or severity of cancer in the subject (Claim 34), or that the method reduces cancer symptoms and/or tumor loads in the subject. Since those outcomes are recited to occur in the subject, it is clear that the methods are methods of treating. This interpretation is consistent with the contemplated use of these methods as treatment claims in the Abstract of the Specification.
The broadest reasonable interpretation (BRI) of the method of Claim 11 is that it encompasses depleting, degrading, or inhibiting PIP4K2C in one or more cells of a subject. The method can be used to inhibit any PIP4K2C in any cell, including inside a subject.
The BRI of Claim 14 is that the method comprises contacting a binding moiety—any binding moiety—with the PIP4K2C, the binding moiety is directly or indirectly linked to an agent that signals cells to degrade the PIP4K2C, and contacting the binding moiety with PIP4K2C will result in degradation of PIP4K2C.
The BRI of the method of Claim 33 is that the depleting/degrading/inhibiting PIP4K2C in one or more cells of a subject will treat any of the recited conditions—cancer, immune deficiency, autoimmune disease, infection or a combination thereof—in a subject who has or is suspected of having any of those conditions. The BRI of Claim 34 is that depleting/degrading/inhibiting PIP4K2C in one or more cells of a subject will reduce the onset or severity of cancer in the subject. The BRI of Claim 35 is that depleting/degrading/inhibiting PIP4K2C in one or more cells of a subject will reduce cancer symptoms and/or tumor loads in the subject by at least 20%.
The nature of the invention of Claim 11 is a method, including a method of treatment, by depleting/degrading/inhibiting PIP4K2C in one or more cells of a subject. The nature of the invention of Claim 14 is a method of degrading PIP4K2C in one or more cells of a subject by contacting any binding moiety with PIP4K2C, wherein the binding moiety is directly or indirectly linked to an agent that signals cells to degrade the PIP4K2C, and that contacting the binding moiety with PIP4K2C will result in degradation of PIP4K2C. The nature of the invention of Claims 33-35 is a method wherein depleting/degrading/inhibiting PIP4K2C in one or more cells of a subject will treat any cancer, immune deficiency, autoimmune disease, infection or a combination thereof in any patient who has or is suspected of having any of those conditions, will reduce the onset of the cancer, and will reduce cancer symptoms by at least 20%. A skilled artisan would not be able to use the method as claimed with a reasonable expectation of success based solely on what is disclosed in the specification.
The problems are as follows:
It would not be possible to successfully use the methods in a subject in vivo.
Contacting any binding moiety with the PIP4K2C doesn’t mean the binding moiety would bind PIP4K2C.
It would not be possible to use the method to treat any of the conditions recited in Claim 33 or treat them in a subject who is merely suspected of having any of the conditions.
It is not possible to know what the time of cancer onset would have been so it is not possible to know if it’s been reduced.
It is not possible to reduce cancer symptoms by 20% because some cancer symptoms aren’t quantifiable.
The state of the art and prior art, the level of one of ordinary skill, and the level of predictability in the art: The prior art indicates the full scope of the claims isn’t enabled.
Regarding point (1), the art of Minikel (2015. Chemical biology 05: Using small molecules to understand life processes. CureFFI.org. Accessed on 23 July 2026, “Minikel”) teaches (p. 1 ¶4) it is important not to assume that genetic and small molecule perturbations will always give identical results. The art of Sangree (2020. Not all loss-of-function approaches are created equal: differential cellular responses to small molecule inhibition, acute CRISPR perturbation, and chronic genetic knockout. Blog post on SpringerNature Research Communities. Accessed on 23 July 2026, “Sangree”) teaches the same: (¶1) Small molecule inhibitors and genetic knockouts are widely deployed to find and characterize potential drug targets. These loss-of-function approaches often produce similar phenotypes, but as our recent study shows, there can be substantial differences. Sangree teaches that (same ¶) unsurprisingly [emphasis added] the differences between approaches were not uniform, and were specific to the gene, perturbed pathway, or cell line. Sangree teaches (¶2) the differences between acute and chronic knockout can be notable and (¶3) small molecules can produce different phenotypes than a genetic knockout because the target can remain present in small molecule inhibition but complete loss of the protein occurs in genetic knockout. Sangree teaches (¶5) a single experimental approach will likely not paint a complete picture, and thus it may be beneficial to conduct both genetic and small molecule screens in order to characterize new drug targets, and their potential inhibitors. Minikel’s and Sangree’s teachings indicate that, in general, results from genetic knockout do not reliably predict results of small molecule inhibition.
In addition, Krishnan (et al. 2026. The multifaceted phosphatidylinositol 5 phosphate 4-kinase proteins: molecular properties and biological functions. BBA Molec. Cell Biol. Lipids 1871:159698, “Krishnan”) teaches (5. Enzymology of PIP4K-5.1. PI5P as a substrate ¶2) experimental observations indicate that the level of in vitro kinase activity of PIP4K2C may not be a direct reflection of in vivo function or that even minimal levels of PIP4K2C enzyme activity may be sufficient to support function in vivo. Krishnan’s teachings indicate that Minikel’s and Sangree’s teachings apply specifically to PIP4K2C because even minimal levels of PIP4K2C enzyme activity may support function in vivo. An artisan would readily understand that, in contrast to total genetic knockout, small molecule inhibition in vivo will leave some amount of functional PIP4K2C. That substantiates the point that results from genetic knockout do not reliably predict results of small molecule inhibition, particularly in vivo.
Regarding point (2), Wills (et al. 2023. A novel homeostatic mechanism tunes PI[4,5]P2-dependent signaling at the plasma membrane. J. Cell Sci. 136:jcs261494, “Wills”) teaches (§PIP4Ks are low-affinity sensors of PM PI[4,5]P2 ¶4) the enzyme Mss4 (which, as an enzyme, possesses binding capability and, therefore may be considered a binding moiety) does not bind to PIP4Ks. A person of ordinary skill would understand that indicates it is simply not possible to degrade PIP4K2C by contacting the binding moiety Mss4 (wherein Mss4 is directly or indirectly to an agent that is an E3 ligase or any other substance that signals cells to degrade whatever it’s bound to) with PIP4K2C because Mss4 is experimentally shown to not bind PIP4Ks. Furthermore, an artisan would readily understand that there exist in the world numerous compounds that can be broadly considered to be a binding moiety and it is plainly evident that any of them cannot be expected to bind PIP4K2C. For example, MedChemExpress (PROTAC BRD9-binding moiety 1. Cat. No.: HY-107445. Accessed on 23 July 2026, “MedChem”) offers for sale PROTAC BRD9-binding moiety 1 which is a compound that binds to BRD9, and used for inhibiting BRD9 activity, based on PROTAC. That product is clearly a binding moiety but there is absolutely no evidence it is capable of binding to PIP4K2C, or that contacting BRD9-binding moiety 1 (wherein it is directly or indirectly linked to an agent that is, e.g., an E3 ligase) with PIP4K2C will signal to cells to degrade the PIP4K2C. Therefore an artisan would reasonably conclude it is not possible to use the full scope of Claim 14 with any reasonable expectation of success.
Regarding point (3), the discussion in the next § discusses that there is no evidence of inhibiting PIP4K2C to treat any immune deficiency, autoimmune disease, infection, or combination thereof, let alone in any patient. As discussed above, Sangree teaches inhibitor responses can be specific to a particular cell line. In addition, the claim recites that the subject is only suspected of having those conditions. A person of ordinary skill would understand it is not possible to treat a condition if it is not present, and suspicion of a condition is not evidence of having the condition.
Therefore an artisan would determine that using the claimed method to treat any of the claimed conditions is unpredictable.
Regarding point (4), Qian (2010. Exploration of the postponing mechanism that delays carcinoma onset. Cancer Cell Int. 10:38, “Qian”) teaches (§Presentation of hypothesis) it is possible that there are molecules that control cancer onset. That indicates it isn’t even known that it is possible to delay cancer onset, only that such a thing is possible. Qian also teaches:
(§Abstract) Animal models will be helpful to test whether the absence or presence of the postponer molecules can alter the onset age of spontaneous tumors. If this hypothesis is true, by amplification of the postponing mechanism we might be able to significantly delay the onset of tumors, so that individuals carrying cancer susceptibility traits could gain an additional significant period of cancer-free life.
Qian indicates (§Implications of hypothesis) these postponer molecules aren’t known to exist. Qian teaches (§Testing the hypothesis, entire §) testing the hypothesis requires comprehensive studies followed by in vitro functional studies involving numerous approaches to confirm biological impacts of the identified postponer candidates and then tests in animal models.
An artisan would understand that determining whether the onset of cancer is reduced is no small task and the art of doing so—let alone the art of actually reducing the onset—is in fact still in the hypothetical stage. Therefore a person of ordinary skill would reasonably determine that it is not possible to reduce the onset of cancer.
Regarding point (5), Claim 35 recites a 20% reduction in cancer symptoms. The American Cancer Society (2025. Signs and Symptoms of Cancer. Accessed on 23 July 2026, “ACS”) teaches (§Common signs and symptoms of cancer) a list of common signs and symptoms of cancer which includes eating problems, such as not feeling hungry. ACS teaches (§Signs vs. symptoms) a sign can be seen or measured by someone else, such as a new spot on the skin, a fever, or a low blood count. That is contrasted with a symptom which is felt or noticed by the person who has it, such as body aches, chills, or feeling tired. An artisan would readily understand that there is no objective way to quantify many feelings. Therefore it is not possible to determine that the claimed method can reduce cancer symptoms in a subject by at least 20%.
Altogether, the above discussion of the state of the art indicates that although the skill level of an artisan is high, using the full scope of the claims as written would be unpredictable.
The amount of direction provided by the specification and the existence of working examples: What is enabled by the working examples and the prior art is narrow compared to the breadth of the claims. Applicant’s examples (start on p. 51 ¶5) show only experiments wherein a Pip4k2c gene is inhibited or knocked out. None of the examples shows or discusses any kind of inhibitor that inhibits or induces degradation of PIP4K2C protein.
Regarding Claim 11, since nothing in the Spec. shows using small molecules to deplete/degrade/inhibit PIP4K2C protein in a subject and since Minikel teaches it is important not to assume that genetic and small molecule perturbations will always give identical results and Krishnan teaches even minimal levels of PIP4K2C enzyme activity may be sufficient to support function in vivo, a person of ordinary skill in the art would determine that successfully using the method to deplete/degrade/inhibit PIP4K2C in a living organism in vivo is unpredictable.
Regarding Claim 14, since nothing in the Spec. shows contacting a representative number of binding moieties (including binding moieties that only contact but don’t actually bind PIP4K2C) with PIP4K2C results in PIP4K2C degradation, an artisan would determine that successfully using the full breadth of the method comprising contacting any binding moiety with PIP4K2C and thereby degrading PIP4K2C is unpredictable.
Regarding Claims 33-35, the examples do show that tumor growth is slowed in mice in whom the pip4k2c gene is knocked out (Figs. 1-8, 10, 13). Those examples use xenograft tumors produced from many different cancer cell types. Some examples (e.g., Figs. 3-4) show that mice wherein the pip4k2c gene is knocked out are indeed resistant to development of cancer when cancer cells are intravenously administered to the mice. The examples do not show inhibiting or degrading PIP4K2C protein to treat any immune deficiency, autoimmune disease, infection, or combination thereof, let alone in any patient. The Spec’s examples don’t enable preventing cancer in a subject by administering an inhibitor of PIP4K2C protein because Applicant hasn’t shown inhibiting PIP4K2C (vs. removing it entirely) prevents cancer onset in a subject. Applicant hasn’t shown inhibiting PIP4K2C treats any immune deficiency, autoimmune disease, infection, or combination thereof.
Furthermore, the claims aren’t enabled because the Spec. discloses (Fig. 12 and p. 8 ¶3) deletion of the Pip4k2c gene from some immune cell types didn’t have any effect on tumor size. Furthermore, the claims are not enabled because the art cautions against assuming that genetic knockout and pharmacological inhibition will give the same results. The art of Qian teaches that delaying onset of cancer requires certain evidence and the Spec. doesn’t provide that evidence for the full scope of the claims, namely depleting/degrading/inhibiting PIP4K2C by any means including using a small molecule inhibitor. The art of ACS teaches that some cancer symptoms are based on subjective feeling which a person of ordinary skill can readily understand is unquantifiable, so it is not possible to determine that any cancer symptom was reduced by 20%. Therefore an artisan would determine that successfully using the full breadth of the claims is unpredictable.
Although the skill level of an artisan is high, the Spec. doesn’t provide evidence to overcome the doubts raised by the art which teaches genetic and small molecule perturbation often yield different results, PIP4K2C is inhibited differently in vivo than in vitro, certain criteria are necessary to demonstrate cancer onset is delayed, and some cancer symptoms aren’t quantifiable. Everything described above teaches that an artisan would reasonably determine that successfully using the full scope of the claimed method is unpredictable and the Spec. doesn’t provide guidance for overcoming that unpredictability.
Since the art of International Publication No. WO 2020/010227 (published 09 January 2020, “WO227”) discloses bifunctional molecules that bind PIP4K2C and comprise an agent that signals cells to degrade whatever is bound to the agent, wherein the agent is cereblon; the art of Clarke (et al. 2015. The function of phosphatidylinositol 5-phosphate 4-kinase γ [PI5P4Kγ] explored using a specific inhibitor that targets the PI5P-binding site. Biochem. J. 466:359, “Clarke”, of record on IDS) shows (§Abstract) the small molecule NIH-12848 binds and inhibits PIP4K2C in vitro; and the art of US Patent Application Publication No. US 2019/0350964 (published 21 November 2019, “App964”, of record on IDS) teaches (Fig. 1I) the small molecule a131 reduces tumor size by 20% in mice, the claims can be considered enabled for those agents and outcomes.
The quantity of experimentation needed to make or use the invention: The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given the above discussion of the state-of-the art, an artisan of ordinary skill would not be able to use the invention as claimed with a reasonable expectation of success. The amount of experimentation required for enabling guidance commensurate in scope with what is claimed goes beyond what is considered “routine” within the art and constitutes undue further experimentation in order to successfully use the full scope of the methods to use any kind of deplete/degrader/inhibitor to deplete/degrade/inhibit PIP4K2C in a subject in vivo (Claim 11), to degrade PIP4K2C by contacting any binding moiety with PIP4K2C (Claim 14), to treat a subject who is suspected of having cancer, immune deficiency, autoimmune disease, infection, or a combination thereof, (Claim 33), to reduce the onset of cancer in the subject (Claim 34), or to reduce cancer symptoms in the subject by at least 20% (Claim 35) with any reasonable expectation of success.
Claims 11, 13-14, 17-19, and 32-35 are rejected for those reasons. Claims 13-19, 21-25, and 31-35 are rejected because they depend from Claims 11, 14, and/or 33 and don’t remedy the issues.
In conclusion, the specification and prior art provide enablement for:
Claim 11: an in vitro or ex vivo method of inhibiting Phosphatidylinositol-5-Phosphate 4-Kinase Type 2 Gamma (PIP4K2C), the method comprising administering an inhibitor of PIP4K2C protein, wherein the inhibitor of PIP4K2C protein is either NIH-12848 or a131.
Claim 14: The method of Claim 11, wherein degrading PIP4K2C comprises contacting a cell comprising the PIP4K2C with a compound that comprises a binding moiety that is directly or indirectly linked to cereblon, wherein the binding moiety is either NIH-12848 or a131.
Claim 33a: An in vitro or ex vivo method of treating cancer in an organoid or in cells of a subject by administering to the organoid or cells an inhibitor of PIP4K2C protein, wherein the inhibitor of PIP4K2C protein is either NIH-12848 or a131, and wherein the cells are not B-cells, T-cells, or natural killer cells.
Claim 33b: A method of treating cancer in a subject by administering to the subject an inhibitor of PIP4K2C protein, wherein the inhibitor of PIP4K2C protein is a131, and wherein the cancer is not a cancer of B-cells, T-cells, or natural killer cells.
Claims 34-35: The method of Claim 33b, wherein administering the inhibitor of PIP4K2C protein reduces tumor size by at least 20% vs. control.
To overcome a prima facie case of lack of enablement, applicant must present argument and/or evidence that the disclosure would have enabled one of ordinary skill in the art to make and use the claimed invention at the time of filing. [emphasis added.]
MPEP §2164.05
Specification Must Be Enabling as of the Filing Date [R-07.2022]
Whether the specification would have been enabling as of the filing date involves consideration of the nature of the invention, the state of the prior art, and the level of skill in the art. The initial inquiry is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains. The nature of the invention becomes the backdrop to determine the state of the art and the level of skill possessed by one skilled in the art.
The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. The relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed. See MPEP § 2164.05(b). See Pac. Biosciences of Cal., Inc. v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir. 2021). [emphasis added.]
MPEP §2164.05(a)
Claim Rejections - 35 USC § 112b
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 11, 13-19, 21-25, and 31-35 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.
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173. In the present instance, Claims 11, 13-19, 21-25, and 30-35 recite PIP4K2C/Pip4k2c, and pip4k2c. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is not clear whether the claims are talking about PIP4K2C/Pip4k2c protein or the Pip4k2c/pip4k2c gene. The Spec. does not provide any clarity because nomenclature is inconsistent throughout. The Abstract refers to compositions and methods for inhibiting, degrading, knocking down or knocking out pip4k2c nucleic acids or Pip4k2c protein and the entire claim set recites a mix of PIP4K2C (e.g., Claim 11), Pip4k2c (withdrawn Claim 6), and pip4k2c (e.g., Claim 22). Therefore an artisan wouldn’t understand what the claims encompass or how to carry out the method steps. Each term should be used consistently.
Claims 11, 13-16, 18-19, and 21-24 are rejected for those reasons. Claims 11, 13-19, 21-25, and 30-35 are rejected because they depend from Claims 11, 13-16, 18-19, and/or 21-24 and do not remedy the issues. In the interest of compact prosecution, the examined claims are interpreted to recite depleting/degrading/inhibiting/inhibiting function of PIP4K2C/Pip4k2c protein.
Claim 14 recites the limitation "…wherein degrading PIP4K2C comprises contacting a binding moiety with the PIP4K2C wherein the binding moiety is directly or indirectly linked to an agent that signals cells to degrade the PIP4K2C bound to the agent" in L1-3. There is insufficient antecedent basis for this limitation in the claim because the claim doesn’t recite any PIP4K2C bound to any agent. The claim recites only contacting the PIP4K2C with a binding moiety that is directly or indirectly linked to an agent that signals cells to degrade the PIP4K2C bound to the agent. Contacting something with a binding moiety doesn’t mean those two things bind so the claim doesn’t recite that the PIP4K2C is bound to any agent. Therefore there is insufficient antecedent basis for the PIP4K2C bound to the agent.
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173. In the present instance, Claim 14 recites …wherein degrading PIP4K2C comprises contacting a binding moiety with the PIP4K2C wherein the binding moiety is directly or indirectly linked to an agent that signals cells to degrade the PIP4K2C bound to the agent. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is unclear how a cell is signaled to degrade the PIP4K2C bound to the agent because nothing in the claim recites that the agent or the binding moiety is bound to or binds to PIP4K2C. The claim recites only that the binding moiety is contacted with PIP4K2C which doesn’t mean the two things bind or that the binding moiety is capable of binding PIP4K2C. The Spec. never defines “binding moiety” to mean something that specifically or directly binds PIP4K2C.
Claim 14 is rejected for those reasons. Claims 15 and 17-19 are rejected because they depend from Claim 14 and do not remedy the issues. In the interest of compact prosecution, for applying prior art, the claims are interpreted to mean that the binding moiety binds PIP4K2C.
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173. In the present instance, Claim 17 recites the binding moiety is indirectly linked to the agent via hydrogen bonding, hydrophobic interaction, steric interaction, hydrophilic interaction, or a combination thereof. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is unclear what is linked to what and how they are joined. It is unclear what “indirectly linked” means. It is unclear what it means to be linked via hydrogen bonding, hydrophobic interaction, steric interaction, or hydrophilic interaction because those kinds of linkages change depending on environmental conditions and the claim doesn’t specify those environmental conditions.
Claim 17 is rejected for those reasons. Claim 19 is rejected because it depends from Claim 17 and does not remedy all the issues. In the interest of compact prosecution, the claims are interpreted to mean the binding moiety is linked to the agent that signals cells to degrade the PIP4K2C through a linker that comprises hydrogen bonding, hydrophobic interaction, steric interaction, hydrophilic interaction, or a combination thereof, at physiological conditions.
Claim 24 recites the limitation "the PIP4K2C protein" in L2. There is insufficient antecedent basis for this limitation in the claim because none of the claims from which Claim 24 depends recites any PIP4K2C protein.
In the interest of compact prosecution, the claims are interpreted to mean that the depleting/degrading/inhibiting PIP4K2C recited in Claim 11 means depleting/degrading/inhibiting PIP4K2C protein.
The term “is suspected of having… [any or a combination of the recited diseases]” in Claim 33 is a relative term which renders the claim indefinite. The term “is suspected of having… [any or a combination of the recited diseases]” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term is indefinite because it doesn’t disclose any criteria for having such suspicion or whose suspicion is relied upon.
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173. In the present instance, Claim 33 recites wherein the subject… is suspected of having… [any or a combination of the recited diseases]. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is not clear who suspects the patient of having any or a combination of the recited diseases or what their credentials are. Is the method suitable to use in any hypochondriac?
Claim 33 is rejected for those reasons. Claim 34 is rejected because it depends from Claim 33 and doesn’t remedy the issues. In the interest of compact prosecution the claim is interpreted as reciting the subject has any of the recited conditions.
The term “the method… reduces the onset or severity of cancer in the subject” in Claim 34 is a relative term which renders the claim indefinite. The term “the method… reduces the onset or severity of cancer in the subject” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is simply not possible to know whether the onset of cancer is reduced because it is not possible to know when onset would have occurred.
In the present instance, Claim 34 recites the method… reduces the onset or severity of cancer in the subject. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. The claims and Spec. do not disclose how to determine whether onset of cancer is reduced.
Claim 34 is rejected for those reasons. In the interest of compact prosecution the claim is interpreted as reciting: the method of Claim 33 wherein depleting/degrading/inhibiting PIP4K2C reduces tumor size or number of cancer cells (i.e., compared with either control-treatment or tumor size/cancer cell number before treatment).
The term “the method… which reduces cancer symptoms in the subject by at least 20%” in Claim 35 is a relative term which renders the claim indefinite. The term “the method… which reduces cancer symptoms… in the subject by at least 20%” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear how an artisan would reduce symptoms in a subject by at least 20%. It is not clear what it means to reduce symptoms in a subject by at least 20%.
In the present instance, Claim 35 recites the method… which reduces cancer symptoms in the subject by at least 20%. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is not clear how an artisan would reduce symptoms in a subject by at least 20%. It is not clear what it means to reduce symptoms in a subject by at least 20%.
Claim 35 is rejected for those reasons. In the interest of compact prosecution the claim is interpreted as reciting any cancer symptom is reduced by any amount vs. before treatment or vs. control treatment.
Claim Rejections - 35 USC § 112d
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 13-19 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.
Claims 13-19 depend from Claim 12 but they don’t incorporate all the limitations of Claim 12 because Claim 12 recites deleting/degrading/mutating a genomic site encoding… and Claims 13-19 recite degrading PIP4K2c protein. In the interest of compact prosecution Claims 13-14 are interpreted to depend from Claim 11.
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 § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim(s) 11, 13-16, 18, 21-24, and 31-35 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by International Publication No. WO 2020/010227 (published 09 January 2020, “WO227”).
WO227 teaches (§Abstract) compounds, compositions thereof, and methods of using them for the targeted degradation of proteins and (¶8) to treat cancer. WO227 teaches (¶2-8) cereblon is a key player in the ubiquitin–proteasome pathway (UPP) because it targets proteins bound to it for ubiquitnation and degradation by the proteasome. WO227 teaches (¶7-8) small molecules that specifically target a target protein are important because they avoid non-specific effects. WO227 teaches (¶7) compounds that induce selective protein degradation induce inactivation of the protein of interest upon addition to cells or administration to an animal.
WO227 teaches (¶7-11) bifunctional compounds that link a cereblon-binding moiety to a ligand that binds a targeted protein, that the ligand that binds the targeted protein can be a small molecule, and using these compounds to treat cancer. A schematic of their concept (¶11) is shown here:
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113
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wherein TBM binds the targeted protein, L is a linker that connects TBM to UBM, and UBM is a ubiquitin binding moiety capable of binding to a ubiquitin ligase such as an E3 ubiquitin ligase (e.g. cereblon). WO227 teaches (¶9) that virtually any protein can be targeted with their compounds, and their compounds can be used to induce degradation/inhibition of virtually any protein, and that an effective amount of their compounds can be used to treat or ameliorate a disease such as cancer. WO227 teaches (¶205) TBM groups according to the present invention include, for example, any moiety which binds to a protein specifically (binds to a target protein)… .
Regarding Claim 11: WO227 teaches (¶292) embodiments wherein compounds of their invention induce ubiquitination and degradation of a target protein that is PIP4K2C. WO227 teaches (¶13-14) their compounds can be incorporated to pharmaceutically acceptable compositions and used in vitro or in vivo to treat diseases/disorders/conditions. WO227 teaches (¶332) contacting a biological sample with their compounds or a composition comprising their compounds. Therefore WO227 anticipates Claim 11.
Regarding Claim 13: the compound shown above can be considered to be a degrader compound since it marks a target protein for degradation. Therefore WO227 anticipates Claim 13.
Regarding Claims 14-15: portions of WO227 (discussed above) describe that the reference teaches the compound must come into contact with the target so that the TBM binds to the target protein (i.e., PIP4K2C). The figure shown above shows that the TBM is indirectly linked to UBM which is an agent that signals cells to degrade what’s bound to it (i.e., in this case, the PIP4K2C bound to the TBM small molecule. Those discussions indicate that UBM, which signals degradation, is an E3 ubiquitin ligase. Therefore WO227 anticipates Claims 14-15.
Regarding Claim 16: as discussed above, WO227 teaches (¶8):
small molecule therapeutic agents that leverage or potentiate cereblon’s substrate specificity and, at the same time, are “tunable” such that a wide range of protein classes can be targeted and modulated with specificity would be very useful as a therapeutic. Accordingly, there remains a need to find bifunctional compounds that are protein degraders useful as therapeutic agents.
As discussed, WO227 teaches (¶11, ¶292) those bifunctional compounds and an embodiment wherein the compounds target PIP4K2C. Therefore WO227 anticipates Claim 16.
Regarding Claim 18: using the bifunctional compounds as described in WO227 would require preparing them, which means an interaction (i.e., via a linker) between the binding moiety (i.e., TBM) and the agent (i.e., UBM) occurs before the binding moiety makes contact with PIP4K2C. Therefore WO227 anticipates Claim 18.
Regarding Claims 21-23, inducing degradation of PIP4K2C using the WO227 compounds would comprise inhibiting its function, inducing degradation of PIP4K2C using the WO227 compounds would comprise inhibiting it, and (as discussed) WO227 teaches small molecules that bind the targeted protein. Broadly speaking, degrading a protein inhibits its function and serves to inhibit the protein because the protein is no longer present to function. To that point, the instant Spec. teaches (p. 29 ¶5-6) methods for degradation or inhibition of PIP4K2C include inducing E3 ubiquitin ligase activity to the protein. Therefore, WO227 anticipates Claims 21-23.
Regarding Claim 24, as discussed, WO227 teaches targeting PIP4K2C and teaches (¶8, ¶205) specificity in target-binding is crucial; therefore WO227 anticipates Claim 24.
Regarding Claims 31-32: As discussed, WO227 teaches (¶13-14) using their compounds in vitro or in vivo; therefore WO227 anticipates Claims 31-32.
Regarding Claim 33: WO227 teaches (¶287) using their compounds to treat cancer; therefore WO227 anticipates Claim 33. WO227 also teaches using their compounds to treat (same ¶) autoimmune diseases or (¶286) microbial infection.
Regarding Claims 34-35: WO227 teaches (¶282) “treat” means delaying onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof and (¶283) treating various cancers. As discussed, WO227 teaches using their compounds to treat cancer. Therefore WO227 anticipates Claims 34-35.
Claims 11, 13-19, 21-25, and 31-35 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by International Publication Number WO 2020/210686 (published 15 October 2020, “WO686”, of record on IDS).
The applied reference has a common inventor and applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
WO686 teaches (p. 22 ¶2) inhibiting or degrading PIP4K2C. WO686 teaches (pp. 22-23 ¶2-4; p. 46 ¶2-4; p. 80 items 10-12; p. 87 items 1-2, 4-5, 11-19, 22, 27, and 29) all the limitations of Claims 11, 13-19, 21-25, and 31-35.
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.
Claim(s) 11, 13-16, 18, 21-25, and 31-35 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication No. WO 2020/010227 (published 09 January 2020, “WO227”) as applied to Claims 11, 13-16, 18, 21-24, and 31-35 in the 102 rejection above, and further in view of Clarke (et al. 2015. The function of phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ ) explored using a specific inhibitor that targets the PI5P-binding site. Biochem. J. 466:359, “Clarke”, of record on IDS) and US Patent Application Publication No.: US 2019/0350964 (published 21 November 2019, “App964”, of record on IDS).
The teachings of WO227 as applicable to Claim(s) 11, 13-16, 18, 21-24, and 31-35 have been described in the 102 rejection above.
WO227 teaches compounds and methods for degrading or inhibiting PIP4K2C in cells of a subject by administering a bifunctional compound whose TBM side binds to PIP4K2C and whose UBM side is a cereblon which forms an E3 ubiquitin ligase complex with Cullin4 and signals a cell to degrade the PIP4K2C.
WO227 does not explicitly teach an example and structure of a specific small molecule that specifically binds to PIP4K2C (i.e., Claims 16 and 23-24). WO227 does not teach the binding moiety/small molecule binds to a PIP4K2C epitope having a sequence with at least 95% sequence identity to a 5-amino acid (AA) to a 30-AA portion of claimed SEQ ID NO 1 (i.e., Claim 25). WO227 does not explicitly provide an example of a method that reduces tumor load in a subject by at least 20%, thereby reducing severity of the cancer (i.e., Claims 34-35).
However, Clarke and App964 teach the limitations that WO227 doesn’t teach.
Regarding Claims 16 and 23-24: Clarke, drawn to a small molecule that specifically binds PIP4K2C, teaches (§Abstract) NIH-12848 specifically inhibits PI5P4Kγ but does not inhibit other PI5P4K isoforms. That indicates that NIH-12848 is a specific binder of PIP4K2C.
Note that PI5P4Kγ is just another term for what is claimed as PIP4K2C. That is clear because the title of the present invention is LOSS OF LIPID KINASE PI5P4K GAMMA RESTRICTS TUMOR GROWTH.
Clarke teaches (§MATERIALS AND METHODS-Enzyme preparation and mutagenesis) the recombinant enzyme they used was PIP4K2C (and prepared from a sequence of UniGene 6280511). Clarke shows (Fig. 1) NIH-12848 binds to PIP4K2C but not (§NIH-12848 is a specific PI5P4Kγ inhibitor) other PIP4K isoforms. That indicates that Clarke teaches limitations of Claims 16 and 23-24.
App964 is drawn to (§Abstract) compounds for inhibiting PI5P4K. App964 teaches (title page) their compound is called a131.
Regarding Claim 25, Clarke didn’t provide any sequence for UniGene 6280511 and the UniGene database is retired. However, App964 teaches (¶28, Table 1) the mRNA and AA sequences of PI5P4KC variant 2. App964 teaches (¶28) PI5P4KC variant 2 is simply another term for PIP4K2C (or PI4P4Kγ) and that their sequences, like those of Clarke, are taken from UniGene 6280511. That means that the App964 sequence for PIP4K2C peptide and the nucleic acid encoding it are the same as what Clarke used in their experiments that determined NIH-12848 specifically binds PIP4K2C—the sequences are taken from UniGene 6280511.
App964 teaches the peptide sequence of PIP4K2C is SEQ ID NO 28. The following alignment shows that App964 SEQ ID NO 28 is 100% identical to claimed SEQ ID NO 1:
US-16-467-937-28
Filing date in PALM: 2019-06-07
Sequence 28, US/16467937
Publication No. US20190350964A1
GENERAL INFORMATION
APPLICANT: National University of Singapore
TITLE OF INVENTION: ANTI-CANCER COMPOUNDS AND USES THEREOF
FILE REFERENCE: MARKS50.004APC
CURRENT APPLICATION NUMBER: US/16/467,937
CURRENT FILING DATE: 2019-06-07
PRIOR APPLICATION NUMBER: PCT/SG20l7/050608
PRIOR FILING DATE: 2017-12-08
PRIOR APPLICATION NUMBER: 10201610300X
PRIOR FILING DATE: 2016-12-08
NUMBER OF SEQ ID NOS: 32
SEQ ID NO 28
LENGTH: 421
TYPE: PRT
ORGANISM: Homo sapiens
ALIGNMENT:
Query Match 100.0%; Score 2194; Length 421;
Best Local Similarity 100.0%;
Matches 421; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MASSSVPPATVSAATAGPGPGFGFASKTKKKHFVQQKVKVFRAADPLVGVFLWGVAHSIN 60 SEQ ID NO 1
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Db 1 MASSSVPPATVSAATAGPGPGFGFASKTKKKHFVQQKVKVFRAADPLVGVFLWGVAHSIN 60 App964 SEQ# 28
Qy 61 ELSQVPPPVMLLPDDFKASSKIKVNNHLFHRENLPSHFKFKEYCPQVFRNLRDRFGIDDQ 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ELSQVPPPVMLLPDDFKASSKIKVNNHLFHRENLPSHFKFKEYCPQVFRNLRDRFGIDDQ 120
Qy 121 DYLVSLTRNPPSESEGSDGRFLISYDRTLVIKEVSSEDIADMHSNLSNYHQYIVKCHGNT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 DYLVSLTRNPPSESEGSDGRFLISYDRTLVIKEVSSEDIADMHSNLSNYHQYIVKCHGNT 180
Qy 181 LLPQFLGMYRVSVDNEDSYMLVMRNMFSHRLPVHRKYDLKGSLVSREASDKEKVKELPTL 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LLPQFLGMYRVSVDNEDSYMLVMRNMFSHRLPVHRKYDLKGSLVSREASDKEKVKELPTL 240
Qy 241 KDMDFLNKNQKVYIGEEEKKIFLEKLKRDVEFLVQLKIMDYSLLLGIHDIIRGSEPEEEA 300
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Db 241 KDMDFLNKNQKVYIGEEEKKIFLEKLKRDVEFLVQLKIMDYSLLLGIHDIIRGSEPEEEA 300
Qy 301 PVREDESEVDGDCSLTGPPALVGSYGTSPEGIGGYIHSHRPLGPGEFESFIDVYAIRSAE 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 PVREDESEVDGDCSLTGPPALVGSYGTSPEGIGGYIHSHRPLGPGEFESFIDVYAIRSAE 360
Qy 361 GAPQKEVYFMGLIDILTQYDAKKKAAHAAKTVKHGAGAEISTVHPEQYAKRFLDFITNIF 420
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Db 361 GAPQKEVYFMGLIDILTQYDAKKKAAHAAKTVKHGAGAEISTVHPEQYAKRFLDFITNIF 420
Qy 421 A 421
|
Db 421 A 421
That means that Clarke’s small molecule, NIH-12848, (which they found specifically binds PIP4K2C) binds with specificity to an epitope of PIP4K2C having at least 95% sequence identity to any portion of claimed SEQ ID NO 1, including a 5- to 30-AA portion of SEQ ID NO 1. That indicates that Clarke as evidenced by App964 teaches limitations of Claim 25.
Regarding Claims 34-35: App964 teaches (Fig. 1, specifically panel 1I and caption at ¶10) Fig. 1 shows selective killing effects of compound a131 in cancer cells and Fig. 1I shows mice bearing tumors were treated with a131 which reduced tumor volume vs. control. The figure shows tumor size was reduced by at least 20%. That indicates that App964 teaches compounds that reduce severity of cancer (Claim 34) and reduce tumor load by at least 20% (Claim 35).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the bifunctional compounds and methods of WO227 with either of the specific small molecules of Clarke or App964 for the benefits of inhibiting PIP4K2C and treating cancer in a subject. One would have been motivated to do so with a reasonable expectation of success because teachings of WO227 indicate their bifunctional compounds are modular and can be modified to incorporate any small molecule that binds any protein of interest. All three references indicate that inhibiting PIP4K2C was of interest and WO227 and App964 teach using their compounds and/or methods to treat cancer. An artisan would have wanted to include the UBM motif of WO227 (as opposed to simply using Clarke’s or App964’s compounds alone) because they would have wanted to completely degrade a detrimental compound, not just inhibit it. Therefore, the limitations of Claims 16, 23-25, and 34-35 (as well as the limitations of Claims 11, 13-15, 18, 21-22, and 31-33) would have been obvious in view of WO227, Clarke, and App964.
Claim(s) 11, 13-19, 21-25, and 31-35 are rejected under 35 U.S.C. 103 as being unpatentable over WO227, Clarke, and App964 as applied to Claims 11, 13-16, 18, 21-25, and 31-35 above, and further in view of Barnaby (et al. 2015. Modular and Chemically Responsive Oligonucleotide “Bonds” in Nanoparticle Superlattices. J. Am. Chem. Soc. 137:13566, “Barnaby”).
The teachings of WO227, Clarke, and App964 as applicable to Claim(s) 11, 13-16, 18, 21-25, and 31-35 have been described above.
WO227, Clarke, and App964 make obvious bifunctional compounds that bind PIP4K2C and target it for degradation.
WO227, Clarke, and App964 do not teach that the binding moiety (i.e., WO227’s TBM moiety) is indirectly linked to the agent that binds PIP4K2C (i.e., WO227’s UBM moiety) via hydrogen bonding (Claim 17) or that the interaction between the binding moiety and the agent occurs after the binding moiety makes contact with PIP4K2C (Claim 19).
However, Barnaby, drawn to using complementary nucleic acids to join two nanoparticles, makes obvious the limitations that WO227, Clarke, and App964 do not teach. Barnaby teaches (§Abstract) using nucleic acid bonds to hold together nanoparticles. Barnaby teaches (same §) using nucleic acids to hold together nanoparticles provides more freedom and great bond versatility. Barnaby teaches (§Introduction ¶1-3) this scheme can be applied to organic and inorganic molecules and proteins, and the unifying element… is the DNA “bond” that programs nanoparticle interactions and drives their assembly…. Barnaby teaches (same § ¶3) nucleic acid hybridization leads to rigid structures and therefore valency, and this sort of hybridization can be used to produce molecular jigsaw puzzles. Barnaby teaches (same §, ¶4) the nature of DNA programmable assembly is well-understood.
Barnaby’s graphical abstract and Fig. 1 show the following figure:
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That figure shows how two nanoparticles or small molecules, including WO227’s TBM and UBM moieties would be joined via hydrogen bonding. Barnaby teaches (Fig. 1 caption) the figure shows:
Nanoparticle superlattices synthesized with modular oligonucleotide bonds. (a) Two-component system where particles A and B are linked by non-self-complementary sticky ends. Four types of oligonucleotide bonds are explored: DNA/DNA (red), RNA/RNA blue), DNA/RNA (dark purple), and RNA/DNA (light purple).
A person of ordinary skill in the art knows that complementary base pairs engage in hydrogen bonds.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the bifunctional compounds and methods for inhibiting PIP4K2C of WO227, Clarke, and App964 with the teachings of Barnaby for the benefit of using complementary nucleic acids to link the TBM and UBM moieties. One would have been motivated to do so with a reasonable expectation of success because WO227 does not teach the linker that joins the two moieties has to possess any particular structure. One would have been motivated to do so with a reasonable expectation of success because using complementary nucleic acids to join the two moieties would provide certain benefits. Joining the TBM and UBM moieties via complementary nucleic acids (which form a structure via hydrogen bonding) would provide a modular design, meaning that the UBM moiety could be easily joined to various PIP4K2C-binding small molecules—Clarke’s NIH-12848 or App964’s a131, or any others—to determine which PIP4K2C-binding small molecule works most effectively in any particular situation. Furthermore, Barnaby indicates (§Introduction ¶1-3) such nucleic acid linkers could be modified to adjust rigidity and to control the orientation of the two moieties in relation to one another.
Regarding Claim 19: such modular design also would have allowed an artisan to administer the PIP4K2C-binding moiety to a cell or patient before administering the UBM moiety. Administering the UBM moiety after administering the TBM moiety would have allowed for the benefit of determining whether degradation (via the ubiquitination pathway) provides further significant PIP4K2C inhibition or otherwise improves disease treatment besides inhibiting PIP4K2C with a small molecule alone.
Therefore the limitations of Claims 17 and 19 (and Claims 11, 13-16, 18, 21-25, and 31-35) would have been obvious in view of WO227, Clarke, App964, and Barnaby.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 11, 13-19, 21-25, and 31-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6-24 of U.S. Patent No. 9493813 (“US813”) in view of International Publication No. WO 2020/010227 (published 09 January 2020, “WO227”), Clarke (et al. 2015. The function of phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ ) explored using a specific inhibitor that targets the PI5P-binding site. Biochem. J. 466:359, “Clarke”, of record on IDS) and US Patent Application Publication No.: US 2019/0350964 (published 21 November 2019, “App964”, of record on IDS), and Barnaby (et al. 2015. Modular and Chemically Responsive Oligonucleotide “Bonds” in Nanoparticle Superlattices. J. Am. Chem. Soc. 137:13566, “Barnaby”).
Although the claims at issue are not identical they are directed to overlapping subject matter because the instant claims are directed to methods comprising depleting, degrading, or inhibiting PIP4K2C in one or more cells of a subject; wherein the method comprises contacting PIP4K2C with a degrader compound that can comprise a binding moiety that binds PIP4K2C and an agent that signals to a cell to degrade the PIP4K2C, wherein the agent can be an E3 ubiquitin ligase and the binding moiety can be a small molecule; wherein the binding moiety and agent can be indirectly joined by various kinds of bonds and can make contact with the PIP4K2C in different orders; wherein the PIP4K2C or its function are inhibited, including by a small molecule that can have specificity for PIP4K2C protein; or to an epitope having identity to claimed SEQ ID NO 1; wherein the method can be performed in vitro or in vivo including in a subject who has cancer or other various conditions; wherein applying the method reduces the severity of the cancer and reduces symptoms and/or tumor load by at least 20%.
The US813 claims are directed to methods for identifying a compound that inhibits PI5P4K (i.e., PIP4K2C in the term of the instant claims) wherein the method includes steps of contacting a cell with a candidate compound, detecting activity of PI5P4K, and determining whether the candidate compound inhibits the target. Those claims explicitly recite inhibiting PIP4K2C.
Both claim sets are directed to methods that include inhibiting PIP4K2C.
The US813 claims don’t recite each element of the instant claims but those would have been obvious in view of the prior art of WO227 (§Abstract, ¶2-14, ¶205, ¶282-283, ¶287, ¶292, ¶332), Clarke (§Abstract, §MATERIALS AND METHODS-Enzyme preparation and mutagenesis; Fig. 1, §NIH-12848 is a specific PI5P4Kγ inhibitor), App964 (§Abstract, ¶28, Table 1; Fig. 1, specifically panel 1I and caption at ¶10), and Barnaby (§Abstract, §Introduction ¶1-4, Fig. 1 and caption), as discussed in the 102 and 103 rejections above.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to modify the methods of the US813 claims with the teachings of WO227, Clarke, App964, and Barnaby for the benefits of producing modular compounds and using compounds identified by the US813 methods to treat cancer. Doing so would have produced the instant claims.
Claims 11, 13-19, 21-25, and 31-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-7, and 9-26 of copending Application No. 17602540 (“App540”) in view of WO227, Clarke, App964, and Barnaby.
Although the claims at issue are not identical they are directed to overlapping subject matter because the instant claims are directed to methods comprising depleting, degrading, or inhibiting PIP4K2C in one or more cells of a subject; wherein the method comprises contacting PIP4K2C with a degrader compound that can comprise a binding moiety that binds PIP4K2C and an agent that signals to a cell to degrade the PIP4K2C, wherein the agent can be an E3 ubiquitin ligase and the binding moiety can be a small molecule; wherein the binding moiety and agent can be indirectly joined by various kinds of bonds and can make contact with the PIP4K2C in different orders; wherein the PIP4K2C or its function are inhibited, including by a small molecule that can have specificity for PIP4K2C protein; or to an epitope having identity to claimed SEQ ID NO 1; wherein the method can be performed in vitro or in vivo including in a subject who has cancer or other various conditions; wherein applying the method reduces the severity of the cancer and reduces symptoms and/or tumor load by at least 20%.
The App540 claims are directed to methods of inhibiting one or more isoforms of PIP4K, including PIP4K2C, wherein the methods comprise inhibiting any PIP4K protein; wherein the methods comprise degrading, modifying, or inhibiting PIP4K2C by contacting it with a binding moiety that has specificity for it, wherein the binding moiety is directly or indirectly linked to an agent that causes its degradation, wherein the binding moiety binds an epitope having a sequence with at least 95% identity to a 5- to 30-AA portion of certain SEQ ID NOs (including App540 SEQ ID NO 10 which comprises 100% identity to instantly claimed SEQ ID NO 1).
Both claim sets are directed to methods of inhibiting PIP4K2C.
The App540 claims don’t recite some limitations of instant Claims 15-19, 23, or 31-35, but those limitations would have been obvious in view of the prior art of: WO227 (§Abstract, ¶2-14, ¶205, ¶282-283, ¶287, ¶292, ¶332), Clarke (§Abstract, §MATERIALS AND METHODS-Enzyme preparation and mutagenesis; Fig. 1, §NIH-12848 is a specific PI5P4Kγ inhibitor), App964 (§Abstract, ¶28, Table 1; Fig. 1, specifically panel 1I and caption at ¶10), and Barnaby (§Abstract, §Introduction ¶1-4, Fig. 1 and caption), as discussed in the 102 and 103 rejections above.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to modify the methods of the App540 claims with the teachings of WO227, Clarke, App964, and Barnaby for the benefits of producing modular compounds and using the App540 compounds to treat cancer. Doing so would have produced the instant claims.
This is a provisional nonstatutory double patenting rejection.
Claims 11, 13-19, 21-25, and 31-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-10, 17-19, 21-26, 28, 32-35, 37-38, 40, and 43-44 of copending Application No. 18269122 (“App122”) in view of Clarke, App964, and Barnaby.
Although the claims at issue are not identical they are directed to overlapping subject matter because the instant claims are directed to methods comprising depleting, degrading, or inhibiting PIP4K2C in one or more cells of a subject; wherein the method comprises contacting PIP4K2C with a degrader compound that can comprise a binding moiety that binds PIP4K2C and an agent that signals to a cell to degrade the PIP4K2C, wherein the agent can be an E3 ubiquitin ligase and the binding moiety can be a small molecule; wherein the binding moiety and agent can be indirectly joined by various kinds of bonds and can make contact with the PIP4K2C in different orders; wherein the PIP4K2C or its function are inhibited, including by a small molecule that can have specificity for PIP4K2C protein; or to an epitope having identity to claimed SEQ ID NO 1; wherein the method can be performed in vitro or in vivo including in a subject who has cancer or other various conditions; wherein applying the method reduces the severity of the cancer and reduces symptoms and/or tumor load by at least 20%.
The App122 claims are directed to compounds that comprise a moiety that binds PIP4K2C linked to a degron that can comprise various structures. An artisan might not know what a degron is or what those structures do, so they would consult the App122 Spec. and find (¶74) it’s a compound that induces degradation and that some of the claimed structures bind to an E3 ubiquitin ligase. The App122 claims recite methods of treating cancer, immune deficiency, autoimmune disease, or infectious disease.
Both claim sets are directed to methods of inhibiting PIP4K2C, including by inducing its degradation via an E3 ubiquitin ligase.
The App122 claims don’t recite some limitations of the instant claims, but those limitations would have been obvious in view of the prior art of: Clarke (§Abstract, §MATERIALS AND METHODS-Enzyme preparation and mutagenesis; Fig. 1, §NIH-12848 is a specific PI5P4Kγ inhibitor), App964 (§Abstract, ¶28, Table 1; Fig. 1, specifically panel 1I and caption at ¶10), and Barnaby (§Abstract, §Introduction ¶1-4, Fig. 1 and caption), as discussed in the 103 rejections above.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to modify the methods of the App122 claims with the teachings of Clarke, App964, and Barnaby for the benefits of producing modular compounds and using the App122 compounds to treat cancer and reduce tumor load in a subject. Doing so would have produced the instant claims.
This is a provisional nonstatutory double patenting rejection.
Claims 11, 13-19, 21-25, and 31-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 and 35-60 of copending Application No. 18559655 (“App655”) in view of Clarke, App964, and Barnaby.
Although the claims at issue are not identical they are directed to overlapping subject matter because the instant claims are directed to methods comprising depleting, degrading, or inhibiting PIP4K2C in one or more cells of a subject; wherein the method comprises contacting PIP4K2C with a degrader compound that can comprise a binding moiety that binds PIP4K2C and an agent that signals to a cell to degrade the PIP4K2C, wherein the agent can be an E3 ubiquitin ligase and the binding moiety can be a small molecule; wherein the binding moiety and agent can be indirectly joined by various kinds of bonds and can make contact with the PIP4K2C in different orders; wherein the PIP4K2C or its function are inhibited, including by a small molecule that can have specificity for PIP4K2C protein; or to an epitope having identity to claimed SEQ ID NO 1; wherein the method can be performed in vitro or in vivo including in a subject who has cancer or other various conditions; wherein applying the method reduces the severity of the cancer and reduces symptoms and/or tumor load by at least 20%.
The App655 claims are directed to compounds that modulate activity of PIP4K2C and to compounds that comprise a moiety that binds PIP4K2C linked to a degron that can comprise various structures. An artisan might not know what a degron is or what those structures do, so they would consult the App655 Spec. and find (¶136) it’s a compound that induces degradation and that some of the claimed structures bind to an E3 ubiquitin ligase. The App655 claims recite methods of treating a disease or disorder by modulating the amount of PIP4K2C.
Both claim sets are directed to methods of inhibiting PIP4K2C, including by inducing its degradation via an E3 ubiquitin ligase.
The App655 claims don’t recite some limitations of the instant claims, but those limitations would have been obvious in view of the prior art of: Clarke (§Abstract, §MATERIALS AND METHODS-Enzyme preparation and mutagenesis; Fig. 1, §NIH-12848 is a specific PI5P4Kγ inhibitor), App964 (§Abstract, ¶28, Table 1; Fig. 1, specifically panel 1I and caption at ¶10), and Barnaby (§Abstract, §Introduction ¶1-4, Fig. 1 and caption), as discussed in the 103 rejections above.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to modify the methods of the App655 claims with the teachings of Clarke, App964, and Barnaby for the benefits of producing modular compounds and using the App655 compounds to treat cancer and reduce tumor load in a subject. Doing so would have produced the instant claims.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 11, 13-19, 21-25, and 31-35 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUTHIE S ARIETI whose telephone number is (571)272-1293. The examiner can normally be reached M-Th 8:30AM-4PM, alternate Fridays 8:30AM-4PM (ET).
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RUTHIE S ARIETI
Examiner
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636
Prosecution Insights