DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 16 April 2026 have been entered. Claims 1-21 were previously pending in the application. No claims were newly cancelled and no new claims were added by Applicant. Claims 1-21 are currently pending in the application. Claims 1 and 12 are independent claims.
The following election of species remains in effect in the instant application:
1) Compounds that modulate PI5P4Kbeta: a. PI5P4Kbeta inhibitors: viii. IMPDH inhibitors: 1. mycophenolic acid (MPA).
Claims 4, 8-11, and 17 remain withdrawn from consideration as being directed to a nonelected species, there being no allowable generic or linking claim.
Claims 1-3, 5-7, 12-16, and 18-21 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2021/020405, filed 02 March 2021, which claims priority to U.S. Provisional Application No. 62/984,026, filed 02 March 2020.
Thus, the earliest possible priority for the instant application is 02 March 2020.
Specification
The objection to the specification of the disclosure for Brief Description of the Drawings does not include a description of each panel is maintained in view of the amendment to the specification. The amendment to the specification of the disclosure filed 16 April 2026 has not been entered.
Applicant amended to specification such that the Brief Description of the Drawings now recites “FIG.” followed by the figure number and the panel letter in place of recitations of the individual panel letters, such as “Fig. 1B” instead of “(B)”. Additionally, the amendment replaces “(A)-(C)” in the description of Figure 13 with “FIG. 13A, FIG. 13B, and FIG. 13C”, thereby reciting each panel letter individually.
However, the amendment to the specification did not include individual descriptions of each of the panels A and B of Figure 6 nor each of the panels A, B, and C of Figure 13. Those panels are still collectively described. The description for Figure 6 reads, “FIG. 6A and FIG 6B show treatment with Link17 increased aggregation of mutant Huntington proteins in the WT-PI5P4Kβ/Pip4K2β-/- cells.” [page 3 of the specification amendment as filed 16 April 2026]. The description for Figure 6 describes A and B together without any individual description of each panel. The description for Figure 13 reads, “FIG. 13A, FIG. 13B, and FIG. 13C show PNT hydrolysis activity of mutant PI5P4Kβ as compared to the WT. The ratios of dephosphorylated/triphosphorylated nucleotides after reaction are shown.” [page 4 of the specification amendment as filed 16 April 2026]. The description for Figure 13 describes A, B, and C together without any individual description of each panel.
Accordingly, Applicant’s amendment to the specification has not overcome the objection identified in the prior action, and the amendment has not been entered.
Claim Objections
*The following new objection is necessitated by amendments to the claims.
Amended independent claim 1 is newly objected to because of the following informalities: claim 1 recites “GTP sensing” in line 3 and “GTP-sensing” in lines 5 and 8 such that recitation of “GTP sensing” in line 3 appears to be missing the hyphen between “GTP” and “sensing”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The rejection of amended and original claims 1-3, 5-7, 12-16, and 18-21 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for multiple issues of indefiniteness is maintained. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claim 1 to recite, “administering to the subject an effective amount of a compound that modulates GTP sensing activity of phosphatidylinositol 5-phosphate 4-kinase beta (PI5P4Kβ) kinase, wherein a PI5P4Kβ inhibitor that decreases the GTP-sensing activity of PI5P4Kβ is administered when the metabolic disorder is a metabolic disorder associated with an underweight bodyweight; and wherein a PI5P4Kβ agonist that increases the GTP-sensing activity of PI5P4Kβ is administered when the metabolic disorder is a metabolic disorder associated with an overweight or obese bodyweight” in lines 2-10. Dependent claim 3 was amended for consistency with the amended independent claim.
Applicant did not amend original independent claim 12. Dependent claim 16 was amended to depend on claim 12 and specifically recite MPA as the inhibitor.
The amendment to independent claim 1 addresses the issues associated with recitation of “when the subject suffers from”. However, independent claims 1 and 12 still each recite, “an effective amount” of a compound that modulates PI5P4Kβ GTP sensing activity [line 3 of claim 1] or of a PI5P4Kβ inhibitor [claim 12 lines 2-3].
Accordingly, Applicant’s arguments have not overcome a finding of indefiniteness under 35 U.S.C. 112(b) for recitation of “an effective amount” in independent claims 1 and 12.
Additionally, Applicant’s amendment to independent claim 1 has introduced new issues of indefiniteness. Amended claim 1 now recites, “a PI5P4Kβ inhibitor that decreases the GTP-sensing activity of PI5P4Kβ” in line 5 and “a PI5P4Kβ agonist that increase the GTP-sensing activity of PI5P4Kβ” in line 8, which is indefinite because it is unclear what is encompassed by decreasing or increasing the GTP-sensing activity of PI5P4Kβ. PI5P4Kβ senses GTP by binding to GTP and subsequently phosphorylating PI(5)P, wherein the GTP sensing results in having more or less kinase activity to phosphorylate PI(5)P [see Sumita et al. 2016, Molecular Cell, 61, 187-198, IDS, Figure 1B, 6C]. As such, under low GTP concentrations, the kinase activity is low and PI(5)P levels are high; whereas under high GTP concentrations, the kinase activity is high and PI(5)P levels are low. As such, PI5P4Kβ is sensing the GTP across a range of GTP concentrations and producing an output dependent on the GTP concentration sensed.
Accordingly, it is unclear what Applicant intends to encompass by “decreasing the GTP-sensing activity of PI5P4Kβ”, such as reducing the GTP binding affinity of PI5P4Kβ, making the PI5P4Kβ kinase activity less sensitive to GTP binding by PI5P4Kβ, or merely reducing the kinase output via a reduction in GTP levels (which still constitutes an appropriate sensing of GTP rather than a decrease in the sensing functionality). The lack of clarity arises particularly in view of Applicant’s claims and election of a PI5P4Kβ inhibitor, MPA, which acts by inhibiting IMPDH to reduce GTP levels in the cell and does not affect the affinity of PI5P4Kβ for binding GTP itself nor the activity of the kinase in response to particular GTP levels. Therefore, MPA does not reduce the GTP-sensing functionality of PI5P4Kβ but merely reduces the output of the GTP sensing activity.
Similarly, it is unclear what Applicant is intending to encompass as increasing the GTP-sensing activity, such as increasing the affinity of PI5P4Kβ for binding GTP, increasing the kinase activity in response to equivalent concentrations of GTP, or merely to increase the kinase activity in response to increases in cellular GTP concentrations which would be within the normal sensing activity of the PI5P4Kβ. Therefore, it is unclear whether Applicant intends to encompass increasing the GTP sensing activity itself or merely the output of the GTP sensing activity.
As such, the metes and bounds of the claim cannot be determined.
Applicant argues that:
“The test for definiteness under 35 U.S.C. § 112(b) is whether "those skilled in the art would understand what is claimed when the claim is read in light of the specification." Orthokinetics, Inc. v. Safety Travel Chairs, Inc., 806 F.2d 1565, 1576, 1 USPQ2d 1081, 1088 (Fed. Cir. 1986) (emphasis added). See also MPEP § 2173.02. In particular, MPEP § 2173.05(b) instructs that the "use of relative terminology in claim language, including terms of degree, does not automatically render the claim indefinite." Further, a claim "is not indefinite if the specification provides examples or teachings that can be used to measure a degree even without a precise numerical measurement." Id.
The Applicant also notes that MPEP § 2173.05(c)III explicitly discusses the phrase "effective amount." As noted, "an effective amount" may or may not be indefinite. However, as explicitly described, "an effective amount" is generally considered definite when read in light of the supporting disclosure and in the absence of any prior art which would give rise to uncertainty about the scope of the claim. Id. In Ex parte Skuballa, 12 USPQ2d 1570 (Bd. Pat. App. & Inter. 1989), the Board held that a pharmaceutical composition claim which recited an "effective amount of a compound of claim 1" without stating the function to be achieved was definite, particularly when read in light of the supporting disclosure which provided guidelines as to the intended utilities and how the uses could be effected.
The Specification as originally filed, on page 9, defines "effective amount" as an "amount sufficient to achieve beneficial or desired results." The Specification also notes that the effective amount "will vary with the metabolic disorder being treated, the age and physical condition of the subject to be treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular therapeutic agents being employed, and like factors within the knowledge and expertise of the attending physician." (emphasis added).
Thus, Applicant submits based on the supporting disclosure and the lack of any reference suggesting that the scope of the claim is unclear, the phrase "effective amount" is definite.” [Remarks page 10-11].
However, this is not agreed.
Although the phrase “effective amount” is considered in light of the supporting disclosure and the prior art in considering definiteness, in the instant case, the disclosure as filed does not provide a standard for ascertaining the metes and bounds of an “effective amount” of the claimed PI5P4Kβ, including the elected MPA. The specification teaches only a single administration of any pharmacological agent to modulate PI5P4Kβ, which is a single dose of MPA to cells in vitro, wherein the dose was sufficient to elicit a small reduction in lysosomal acidification within PI5P4Kβ-/- knockout cells which were transduced with WT PI5P4Kβ [Figure 5]. The specification does not teach any administration of any pharmacological agent to any subject with any condition. The specification does not teach administration of MPA to any subject or cell having any metabolic disorder. The specification does not teach any administration which results in any changes in body weight. As such, the specification does not provide any guidance for any “effective amount” of any agent which would achieve any beneficial or desired results according to the instant method as claimed.
Merely reciting that a physician could figure out what dose to administer, in the absence of any guidance, is not providing guidance as to the metes and bounds of what constitutes an effective dose nor what constitutes a beneficial or desired result achieved by such an effective dose.
As such, the metes and bounds of the claim still cannot be determined.
Therefore, Applicant’s amendments and arguments do not overcome a finding of indefiniteness under 35 U.S.C. 112(b), and the rejection is maintained.
Claim Rejections - 35 USC § 112(a)
The rejection of amended and original claims 1-3, 5-7, 12-16, and 18-21 under 35 U.S.C. 112(a) for failing to comply with the enablement requirement is maintained. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claim 1 to recite, “administering to the subject an effective amount of a compound that modulates GTP sensing activity of phosphatidylinositol 5-phosphate 4-kinase beta (PI5P4Kβ) kinase, wherein a PI5P4Kβ inhibitor that decreases the GTP-sensing activity of PI5P4Kβ is administered when the metabolic disorder is a metabolic disorder associated with an underweight bodyweight; and wherein a PI5P4Kβ agonist that increases the GTP-sensing activity of PI5P4Kβ is administered when the metabolic disorder is a metabolic disorder associated with an overweight or obese bodyweight” in lines 2-10. Dependent claim 3 was amended for consistency with the amended independent claim.
Applicant did not amend original independent claim 12. Dependent claim 16 was amended to depend on claim 12 and specifically recite MPA as the inhibitor.
Amended claim 1 specifies the effect of the claimed compound on modulating PI5P4Kβ, but does not introduce any new limitations which would alter the scope of the claims as elected, wherein the PI5P4Kβ inhibitor is MPA. Accordingly, Applicant’s amendments to claims 1, 3, and 16 have not overcome the enablement rejection under 35 U.S.C. 112(a).
Applicant argues that:
None of the references cited by the Office describe specifically modulating the GTP-sensing activity of PI5P4Kβ, which results in these opposite effects;
Reliance on Whitehead teaching that MPA results in weight gain is incorrect, in that Whitehead at most teaches that lipid accumulation was reduced during differentiation of adipocytes and not in a subject suffering from a metabolic disorder associated with abnormal bodyweight, and further states that MPA treatment promoted an increase in IMPDH expression that is somehow correlated with inhibition of IMPDH, such that a person of ordinary skill in the art would not find the teachings of Whitehead reliable;
The office is not appreciating the kinase-independent scaffolding role of PI5P4Kβ, wherein the scaffolding function suppresses PI3K activation in response to insulin;
Some patients taking MMF (an MPA pro-drug) as an immunosuppressant following renal transplant demonstrated significant decrease in body weight, but those patients were not suffering from a metabolic disorder associated with an underweight bodyweight, which is when an inhibitor of PI5P4Kβ would be used;
The data in the instant application demonstrate the inhibiting PI5P4Kβ, particularly the GTP-sensing activity of PI5P4Kβ, causes weight gain by disrupting key metabolic pathways, including inhibition of lipid metabolism, disruption of lysosomal function, and altered glucose regulation (including increased insulin resistance);
Applicant produces direct and unambiguous evidence and instruction on how the GTP-sensing activity of PI5P4Kβ may be modulated, and the consequences of modulating said activity- namely that inhibiting the GTP-sensing activity of PI5P4Kβ results in decreased fat oxidation, increased lipid accumulation in tissues and a shift towards carbohydrate usage as the primary fuel source, all contributing to weight gain, wherein decreased autophagic activity and lysosomal acidification further exacerbate fat accumulation, leading to obesity-like phenotypes, such that the person skilled in the art would appreciate that these mechanisms can be targeted by compounds that modulate GTP sensing activity in order to treat a metabolic disorder associated with abnormal bodyweight in a subject.
However, this is not agreed.
Regarding Applicant’s argument 1), although Whitehead and Maes are silent specifically with respect to the effects of MPA treatment on PI5P4Kβ, Sumita specifically addresses the role of the lipid kinase PI5P4Kβ as an intracellular GTP sensor for metabolism and tumorigenesis, including the effects of the PI5P4KβF205L mutant on the modulating the GTP-sensing activity of PI5P4Kβ by specifically reducing binding to the GTP analog as well as decreasing GTP-dependent kinase activity [pp 190 col 2 ¶ 2- pp 191 col 1 ¶ 1]. Additionally, the teachings of Whitehead and Maes regarding the effects of MPA is relevant to the instant invention irrespective of their identifications of the specific downstream molecular consequences of the treatments.
Regarding Applicant’s argument 2), Whitehead was cited for teaching the administration of the elected IMPDH inhibitor MPA for treating disorders associated with increased bodyweight (e.g., obesity), such that IMPDH inhibitors are used for the negative regulation of adipogenesis, including down-regulating the differentiation potential and/or proliferation of preadipocytes and/or the accumulation of lipids in adipocytes [0001, 0015, 0133]. Whitehead was also cited for teaching that MPA treatment blocks lipid accumulation and adipocyte differentiation [0041, 0044, 0789-0790, 0792, Figure 9, 12]. Whitehead further teaches the administration of IMPDH agonists for the treatment of metabolic disorders associated with decreased bodyweight, such as cachexia [0016, 0025].
Applicant acknowledges that Whitehead teaches that MPA administration to cells inhibits lipid accumulation in adipocytes [as taught by Whitehead Example 7 ¶ [0789]]. Additionally, Applicant suggests that Example 8 of Whitehead presents a paradox which would make the full disclosure of Whitehead unreliable to an ordinarily skilled artisan. Whitehead teaches that MPA treatment of cells promoted an increase in IMPDH expression which was prevented by co-treatment with guanosine, which serves as a substrate for the salvage pathway of guanine nucleotide biosynthesis and circumvents the requirement for IMPDH dependent de novo synthesis of GTP [0791]. As such, the teachings of Whitehead suggest to an ordinarily skilled artisan that the loss of GTP production via the inhibition of IMPDH by MPA promotes an increase in IMPDH expression as a feedback mechanism by the cell to promote GTP production and remedy the loss; supplementation with guanosine prevents the GTP depletion associated with inhibition of IMPDH, and thus prevents the increase in IMPDH expression associated with the decrease in GTP concentration (or accompanying increase in the balance between GDP and GTP). Accordingly, such teachings to not render Whitehead unreliable to an ordinarily skilled artisan.
Additionally, regarding the lack of Whitehead teaching data for administering MDA to patients having a metabolic disorder associated with low body weight, note that, as discussed above, Whitehead teaches to administer IMPDH agonist for the treatment of metabolic disorders associated with low body weight, such as cachexia, to stimulate adipogenesis [0016, 0025, 0031, 0690]. Whitehead further teaches administering IMPDH antagonists, such as MPA, when reduced adipogenesis is required, such as in the treatment of obesity or conditions of localized abnormal increases in adipogenesis; wherein conditions contemplated in such treatment regimes include pathologies which are associated with or
secondary to, obesity, such as atherosclerosis, hypertension, diabetes including insulin resistance/type II diabetes and endocrine or other metabolic diseases or conditions. Conditions of localized, abnormal increases in adipogenesis may include adipose tumors (lipomas and liposarcomas) and lipomatosis. [0122, 0133]. Therefore, Whitehead teaches the administration of MPA to patients with underlying metabolic disease, but teaches to use them oppositely from the instant claims.
Additionally, as discussed in more detail below, Maes was cited for teaching the effects of administering MPA (via the prodrug MMF) to patients.
Further, as discussed in more detail below, Applicant has not provided any evidence that administering MDA to patients will result in increased body weight, with or without an underlying metabolic disorder.
Regarding Applicant’s argument 3), note that Applicant’s election of mycophenolic acid as an inhibitor of IMPDH reduces GTP production, which thereby affects the GTP sensing function of PI5P4Kβ by reducing the GTP-dependent kinase activity. Accordingly, the effects of MPA on inhibiting PI5P4Kβ are specific to the functions of PI5P4Kβ which are sensitive to GTP levels in the cell. Therefore, discrimination between GTP-sensing kinase activity and kinase-independent scaffolding is already accounted for within the context of specifically using MPA to inhibit GTP-dependent functions of PI5P4Kβ. Note that Whitehead, Maes, and Sumitra were all cited for teachings related to MPA administration to cells and/or patients, which necessarily discriminates between GTP-dependent functions and any GTP/kinase-independent scaffolding functions of PI5P4Kβ.
Regarding Applicant’s argument 4), Maes was cited for teaching that some patients treated with MMF (a pro-drug for MPA) as an immunosuppressant following renal transplantation present with a significant decrease in body weight [Maes et al. 2003, Transplantation, 75(5), 665-672, column 6 ¶ 2]. Although the patients of Maes were not being treated specifically for a metabolic disorder, Maes teaches the effects of MMF/MPA treatment in humans, wherein patients experience severe gastrointestinal side effects which lead to weight loss in the patients. Additionally, Applicant has not provided any evidence that the effects in humans would be different for patients suffering from a metabolic disorder associated with a low body weight compared to patients without any metabolic disorder associated with a low body weight. Maes teaches that malabsorption and other gastrointestinal complications induce weight loss in patients taking MMF/MPA, and Applicant has not shown any weight gain effect in any patients, and particularly has not shown any weight gain effect sufficient to overcome the weight loss effects expected based on the teachings of Maes. Further, as discussed above, Whitehead teaches that MPA is used to promote weight loss, and not to promote weight gain.
Regarding Applicant’s argument 5), Applicant’s provides an extensive discussion of the data presented in the instant disclosure, which indicate that PI5P4Kβ is involved in metabolic pathways. However, some of the extrapolatory conclusions made by Applicant are not supported by the data presented. For example, Applicant asserts that the data presented in Figure 2 demonstrating results of an insulin tolerance test in wild type (WT), PI5P4Kβ-/- knockout, and PI5P4KβF205L/F205L knockin mice demonstrate increased insulin resistance in the PI5P4KβF205L/F205L knockin mice compared to mice. To the extent that any of the data presented in Figure 2E represents significant differences, Fig. 2E actually shows that the PI5P4KβF205L/F205L mice were more sensitive to insulin than the WT mice in that the F205L mutant had a larger initial drop (at 20 and 30 minutes) in blood sugar levels than either the WT or the knockout mice. The increase over the subsequent 1.5 hours merely shows a return to approximately pre-dose levels for both the WT and the F205L knock-in mice, wherein the F205L mice return to the higher basal glucose levels.
The data in presented in instant Example 1 and Figure 1 shows that the PI5P4KβF205L/F205L mice do not exhibit any increased weight compared to WT mice. The data in instant Example 2 and Figure 2A also teaches that only the liver showed histological differences between the PI5P4KβF205L/F205L mice and WT mice, and that body composition was the same for both WT and PI5P4KβF205L/F205L mice. Example 3 and Figure 3C indicate a marginal (~5 g) increase in body weight for the PI5P4KβF205L/F205L mouse fed a high fat diet compared to a WT mouse fed a high fat diet.
Although Applicant observed lipid accumulations in the liver (and only in the liver) in the F205L mutant mouse [instant Example 2, 3, Figure 2A, 3D], Whitehead teaches that inhibition of IMPDH by MPA treatment blocks lipid accumulation in adipocytes and adipocyte differentiation [0041, 0044, 0789-0790, 0792, Figure 9, 12]. Therefore, whereas the instant disclosure suggests the generation of a fatty liver can be achieved by reducing the GTP sensing activity of PI5P4Kβ, which is unlikely to have profound effects to increase bodyweight, Whitehead teaches that MPA administration blocks lipid accumulation in adipocytes, which would be expected by the ordinarily skilled artisan to have a profound effect on body weight given the relative contributions of liver vs. adipocytes to the overall weight potential of a human.
The only data presented for MPA administration is presented in Example 3/Figure 5, wherein primary MEFs from PI5P4Kβ-/- knockout mice or primary MEFs from PI5P4Kβ-/- knockout mice with WT PI5P4Kβ added back were treated with MPA for 2 hours and then stained with Lysotracker®. Under DMSO control treatment conditions, there is no observable difference between the PI5P4Kβ-/- KO and the WT PI5P4Kβ/PI5P4Kβ-/- add-back cells. The addition of MPA appears to result in a small reduction in lysosome acidification in the WT PI5P4Kβ/PI5P4Kβ-/- add-back cells without affecting any change in the KO cells, indicating a potential role for PI5P4Kβ in facilitating MPA-induced de-acidification of lysosomes in vitro. Note that no MPA-treatment data is presented for the F205L mutant or for wild-type cells. Additionally, no quantification of the data presented in Figure 5 is provided. Figure 5 merely shows a single field of view for a single replicate of each of the KO and WT add-back cells for each of the DMSO vehicle control and the MPA treatment conditions. Applicant does not provide any data indicating that MPA administration results in any weight gain in any organism under any conditions.
The data presented in the instant application demonstrates a complex relationship between PI5P4Kβ and maintenance of metabolic homeostasis. However, the data does not show a causative relationship between inhibiting PI5P4Kβ and inducing weight gain in a patient wherein inhibiting PI5P4Kβ causes weight gain in a patient.
Regarding Applicant’s argument 6), as discussed above, Applicant’s data is neither direct nor unambiguous evidence that GTP-sensing activity of PI5P4Kβ may be modulated through inhibition to produce weight gain in a subject. Applicant has provided data generated with a mutant mouse comprising PI5P4Kβ having reduced GTP-binding and reduced GTP-dependent kinase activities and/or with a PI5P4Kβ knockout mouse. Applicant has not provided evidence that pharmacological manipulation of PI5P4Kβ function leads to either weight loss or weight gain.
Further, work from the Inventor’s own research group, Sumita, was cited for teaching that PI5P4Kβ knockout mice have reduced body weight and resistance to obesity induced by high-fat diets [column 18 ¶ 2]. Sumitra also cites a reference, Lamia 2004, for teaching increased insulin sensitivity and reduced adiposity in PI5P4Kβ knockout mice [pg 196 col 1 ¶ 3, pg 198 col 1 ¶ 6]. The instant figures have limited data comparing the F205L mutant with the knockout. Figure 2 shows that the F205L mutant has higher blood glucose levels than the knockout under each of the fed and fasting conditions, that the F205L mutant has a more dramatic response to insulin than the knockout, and that the F205L has a higher spike in blood glucose following a glucose feeding than the knockout which resolves back to pre-feeding levels within 2 hours for both. However, Figure 3 shows that the glucagon response is similar for both; Figure 6 shows that the viability following Nigericin treatment is similar for both; and Figure 7 shows that the autophagic flux following serum starvation and BafA1 treatment is similar for both. Therefore, Applicant’s data indicates that not all phenotypes associated with the knockout are irrelevant with respect to the F205L mutant, which allegedly isolates the GTP sensing functions of PI5P4Kβ from the putative scaffolding functions. Note that Applicant has not provided data demonstrating that scaffolding functions are not affected by the F205L mutant.
Sumita further teaches that PI5P4Kβ GTP sensing is essential for tumorigenesis, wherein tumor growth is inhibited by PI5P4KβF205L mutation, indicating that the GTP-sensing functions of the wildtype PI5P4Kβ promotes tumor growth [pg 193 col 1 ¶ 3- pg 194 col 1 ¶ 1, Figure 6]. Sumitra therefore proposes inhibiting the GTP-sensing activity PI5P4Kβ as pharmaceutical target for cancer therapeutics to inhibit growth [Highlight, abstract, pg 188 col 2 ¶ 2, pg 196 col 2 ¶ 1]. As such, Sumitra teaches that PI5P4Kβ GTP-sensing functions promote growth/ survival of cells.
Applicant has provided no data showing that pharmacological inhibition of PI5P4Kβ GTP sensing functions leads to weight gain in any organism under any condition. Applicant has provided no data for any manipulations of PI5P4Kβ within the context of any metabolic disorder. Applicant has only provided data for mice and cells which are wild-type, PI5P4Kβ-/- knockout, or PI5P4KβF205L/F205L knockin without any metabolic disorders present in the mice. Applicant has additionally only provided in vitro MPA treatment data for PI5P4Kβ-/- knockout MEFs and PI5P4Kβ-/- knockout MEFs with WT PI5P4Kβ added back. Therefore, Applicant has not provided any evidence which would lead an ordinarily skilled artisan to disregard the teachings of Whitehead, Maes, and Sumitra. Accordingly, Applicant has not provided any data which would lead an ordinarily skilled artisan to expect that treating a patient having a metabolic disorder by administering MPA will lead to weight gain in the patient.
Given the teachings of Whitehead, Maes, and Sumitra, the ordinarily skilled artisan at the time of filing would have expected administration of MPA to result in loss of body weight, and not an increase of body weight. As taught by Whitehead, an ordinarily skilled artisan would therefore have used MPA as a treatment for conditions associated with an overweight or obese body weight rather than as a treatment for conditions associated with an underweight bodyweight. Therefore, the ordinarily skilled artisan would have considered treatment of conditions associated with an underweight bodyweight by administration of the IMPDH inhibitor MPA as highly unpredictable.
Applicant’s disclosure does not overcome this art recognized unpredictability as the disclosure does not provide sufficient guidance for treating any subject having a condition associated with an underweight bodyweight using the elected PI5P4Kβ inhibitor (e.g., the IMPDH inhibitor MPA), nor any other inhibitor of PI5P4Kβ GTP sensing activity.
Therefore, in view of the state of the art at the time of filing for using IMPDH inhibitors (e.g., MPA) to treat obesity; the art teachings that PI5P4Kβ knockout mice have reduced body weight, increased insulin sensitivity, and resistance to obesity induced by high-fat diets; the art teachings that some human patients taking MPA experience weight loss side effects; the art recognized unpredictability for treating a condition associated with an underweight bodyweight by administration of MPA; the lack of teachings in the working examples demonstrating the effects of MPA (nor any other drug) on bodyweight; the lack of teaching in the working examples of MPA treatment or PI5P4Kβ activity modulation for any subjects or samples having a metabolic disorder, the limitation of the working examples with regards to bodyweight to the comparison of wild-type mice vs mice having a single point mutation of PI5P4Kβ and lacking any metabolic disorder; and the breadth of the claims; it would have required undue experimentation to practice the methods of treating a metabolic disorder associated with abnormal bodyweight in a subject in need thereof comprising administering to the subject an effective amount of a compound that modulates PI5P4Kβ GTP sensing activity, wherein a PI5P4Kβ inhibitor is administered when the subject has a metabolic disorder associated with an underweight bodyweight without undue experimentation.
Accordingly, the rejection under 35 U.S.C. 112(a) for failing to comply with the enablement requirement is maintained.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
Prosecution Insights