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 .
Status
Claims 34-40 are pending, wherein Claim 40 is newly added. Claims 1-33 are cancelled. Therefore, Claims 34-40 are presented for examination.
Priority
This application is a 371 National Stage Entry of PCT Application No. PCT/EP2018/064282, filed May 30, 2018, which claims priority to European Application No. 17305620.1, filed May 30, 2017.
Information Disclosure Statement
No Information Disclosure Statement(s) was filed.
Withdrawal of Rejections
Claims 34-39 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for “prevention” or “prophylaxis” as previously claimed. Applicant’s amendment and corresponding reply pertaining to the newly added limitation have overcome the scope of enablement rejection made of record in the previous Office Action, specifically, the removal of the limitation to claim 34 that required prevention/prophylaxis of the claimed disease. Therefore, the rejection is hereby withdrawn.
Claim Rejections - 35 USC § 103
Rejection Maintained
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.
A. Maintained - Claims 34-38 and 40 are rejected under 35 U.S.C. 103 as being unpatentable Zha et al. "Lactate Dehydrogenase B Is Critical for Hyperactive mTOR-Mediated Tumorigenesis." Cancer Res; 71(1);13–8. 2011 AACR – cited in 2/23/2024 PTO892) in view of OKAYAMA UNIV. (WO-2014115764-A1 – cited in 2/23/2024 PTO892).
Claimed invention
Claim 34 is drawn to a method for treating a disease associated with a dysregulation of the mTOR pathway, particularly a hamartoma syndrome such as tuberous sclerosis (Claim 37), in an individual having a hyper activation of the mTOR pathway comprising:
selecting an individual with an activation of the mTOR pathway and
administering to the individual a therapeutically effective amount of a compound of formula (I) such as stiripentol,
wherein the compound of formula (I) is not administered in combination with another compound intended to treat tuberous sclerosis, and
wherein the compound of formula (I) inhibits the mTOR pathway (particularly, downstream for the Akt level - Claim 40).
Prior art
Tuberous Sclerosis Complex (TSC) disease is a disease involving multiorgan tumors due to mTOR hyperactivity. The hyperactivity is caused when inactive mutations occur in either TSC1 or TSC2 protein complex, which is the major suppressor of mTOR signaling. See Zha, p. 15, first par. Lactate dehydrogenase B (LDHB) is pivotal for the proliferation and tumor formation of cells with hyperactive mTOR signaling. See Zha p. 18, second column. It is a potential therapeutic target for disorders involving mTOR signaling. See Id.
While Zha teaches TSC involves multiorgan tumors and is caused by hyperactivity of mTOR signaling and further teaches that LDHB, a target for therapy, is pivotal for the proliferation and tumor formation of cells with hyperactive mTOR signaling, Zha does not expressly teach stiripentol.
However, stiripentol is a known drug used for its LDHB inhibitory activity for treating hyperproliferative disorders. For example, OKAYAMA UNIV., teaches stiripentol is a lactate dehydrogenase (LDH) inhibitor, having LDH1 (i.e., LDHB) and LDH5 inhibitory action, can be used as an antitumor agent or as a treatment for metabolic diseases. See Claims 1-6.
One of ordinary skill in the art (POSA) would have found it obvious to select individuals with tuberous sclerosis complex (TSC) and treat them by administering stiripentol because: (a) Zha teaches that TSC is a disease of multiorgan tumors caused by hyperactivity of mTOR signaling and further teaches LDHB (i.e., LDH1) is pivotal for the proliferation and tumor formation of cells with hyperactive mTOR signaling and even further reaches LDHB is a target for therapy, and (b) OKAYAMA UNIV. teaches stiripentol is a known inhibitor of LDH1 (i.e., LDHB) and LDH5 that is used for antitumor activity. The POSA would have had a reasonable expectation of success that 1) stiripentol would provide its LDHB inhibitory activity to a subject with TSC and 2) such inhibitory activity would be beneficial in the treatment of TSC in the subject since LDHB activity is pivotal in the tumorigenesis in cells with hyperactive mTOR signaling such as in TSC. Regarding the limitation “wherein the compound of formula (I) is not administered in combination with another compound intended to treat tuberous sclerosis”, there is no requirement in the prior art that stiripentol is in combination with another agent intended to treat TSC.
The claim limitation reciting that “the compound of formula (I) inhibits the mTOR pathway” defines the claimed method by a functional result of administering the compound, rather than a structural or mechanistic distinction over the prior art.
The prior art is not required to explicitly recognize or describe the functional outcome so long as a POSA would have reasonably expected that inhibiting LDHB using a known LDHB would functionally inhibit mTOR-mediated pathological signaling in diseases characterized by hyperactivation of the mTOR pathway. The functional limitation is satisfied where a POSA would have reasonably expected the claimed functional result based on the teachings of the prior art. Furthermore, in this case, Claim 36 states that the compound of formula (I) that obtains the functional outcome is stiripentol, which is a known LDHB inhibitor. The functional limitation that the compound inhibits the mTOR pathway (including downstream from Akt level as recited in Claim 40) in the context of treating a disease characterized by activation of the mTOR pathway is reasonably satisfied based on the teachings of Zha and Okayama, and does not distinguish the claimed method from the prior art.
Accordingly, the claimed invention as a whole would have been prima facie obvious to one of ordinary skill before the effective filing date of the claimed invention.
Claims 35-36 read on the structure that encompasses stiripentol. OYAMA UNIV. meets these claims by teaching stiripentol.
Claim 37 wherein the disease is TSC, Zha teaches TSC.
Claim 38 further comprising selecting an individual with a hyperactivation of the mTOR pathway before the administering step. Zha identifies individuals with TSC. When taken in combination with OKAYAMA UNIV. as described above, the POSA would have found it obvious to administer stiripentol to impart its LDHB-inhibiting activity. The step of selecting TSC patients for treatment meets the claimed step of selecting the individual with hyper activation of the mTOR pathway because TSC is characterized by activation of the mTOR pathway. As mentioned above, Zha teaches TSC is a disease involving multiorgan tumors due to mTOR hyperactivity.
Response to arguments
Applicant's arguments have been fully considered but have not been found to be persuasive.
Applicant argues that the cited references do not teach inhibition of the mTOR pathway, do not teach inhibition downstream of Akt, and that LDHB inhibition does not cause mTOR inhibition. However, the claims do not require the prior art to expressly disclose inhibition of the mTOR pathway or a mechanism linking LDHB inhibition to mTOR pathway inhibition. The claims recite functional inhibition of the mTOR pathway as a result of administering the compound of formula (I) to treat the subject as claimed. As set for the in the rejection, the prior art suggests that inhibiting LDHB using stiripentol would functionally inhibit mTOR-mediated pathological signaling in diseases characterized by hyperactivation of the mTOR pathway, regardless of whether such inhibition occurs upstream or downstream of Akt. A direct mechanistic causation between LDHB inhibition and mTOR signaling is not required to establish obviousness.
Applicant argues that cancer models are not predictive of hamartoma syndromes such as TSC. However, Zha teaches hyperactivation of mTOR pathway is involved in multiple diseases, including TSC, and identifies LDHB as a therapeutic target in disorders involving mTOR dysregulation. The rejection is based on a shared pathway involved in disease etiology/pathophysiology rather than the exact same tissue or cell type. A POSA would have reasonably extrapolated the therapeutic utility of LDHB inhibition in mTOR-driven disease context, including hamartoma syndromes.
Applicant further argues unexpected results by showing inhibition of mTOR pathway. However, this is considered to be evidence describing how the invention works, not evidence of obtaining an unexpected result. The prior art is not required to precisely predict the intracellular mechanisms by which mTOR pathway inhibition occurs.
Applicant argues that the Examiner stated that the rejection is not based on mTOR inhibition. However, the current rejection is based on the reasonably expectation that inhibiting LDHB using a known LDHB inhibitor, specifically stiripentol, would functionally inhibit mTOR-mediated pathological signaling in disease characterized by hyperactivation of the mTOR pathway. The amendment does not alter the basis of the rejection.
Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
B. Maintained - Claims 39 is rejected under 35 U.S.C. 103 as being unpatentable Zha et al. "Lactate Dehydrogenase B Is Critical for Hyperactive mTOR-Mediated Tumorigenesis." Cancer Res; 71(1);13–8. 2011 AACR – cited in 2/23/2024 PTO892) in view of OKAYAMA UNIV. (WO-2014115764-A1 – cited in 2/23/2024 PTO892) as applied to Claims 34-38 and 40, taken further in view of Inoki et al. (“Dysregulation of the TSC-mTOR pathway in human disease.” Nat Genet 37, 19–24 (2005). https://doi.org/10.1038/ng1494).
Claimed invention
Claim 39 depends from Claim 34, wherein the disease associated with a dysregulation of the mTOR pathway is PTEN-related hamartoma syndrome or Peutz-Jeghers syndrome.
Prior art
The disclosures of Zha and OKAYAMA UNIV. and how they meet the limitations of Claims 34-38 are described above. As previously stated, Zha teaches lactate dehydrogenase B (LDHB) is pivotal for the proliferation and tumor formation of cells with hyperactive mTOR signaling and it is a potential therapeutic target for disorders involving mTOR signaling. See Zha, p. 18, second column. Additionally, OKAYAMA UNIV. teaches stiripentol is a known inhibitor of LDH1 (i.e., LDHB) and LDH5 that is used for antitumor activity. See OKAYAMA UNIV., Claims 1-6.
The combination of Zha and OKAYAMA UNIV., however, does not expressly teach PTEN-related hamartoma syndrome or Peutz Jegher’s syndrome.
High levels of dysregulated mTOR activity (i.e., mTOR hyperactivity) are associated with several hamartoma syndromes, including tuberous sclerosis complex, the PTEN-related hamartoma syndromes and Peutz-Jegher’s syndrome. See Inoki, abstract. Hamartomas are a histologically defined subtype of benign tumor. See Inoki, para. bridging pages 20 and 21. Tuberous sclerosis complex, PTEN-related hamartoma syndromes (Crowden disease, BRRS, proteus syndrome – see para. bridging columns at page 21), and Peutz-Jegher’s syndrome involve tumors in multiple organs and have established links to dysregulated mTOR. See Table 1.
One of ordinary skill in the art would have found it obvious to select individuals with tuberous sclerosis complex (TSC), Peutz-Jegher’s syndrome, or PTEN-related hamartoma syndromes such as Crowden disease, BRRS, or proteus syndrome and treat them by administering stiripentol because:
1) Zha and OKAYAMA UNIV. suggests the use of stiripentol to target LDHB by providing its LDHB-inhibitory activity for treatment of diseases with tumor cells having hyperactive mTOR activity since LDHB activity is pivotal in the tumorigenesis in cells with hyperactive mTOR signaling such as in TSC, and
2) Inoki teaches high levels of dysregulated mTOR activity (i.e., mTOR hyperactivity) are associated with several hamartoma syndromes, including tuberous sclerosis complex, the PTEN-related hamartoma syndromes and Peutz-Jegher’s syndrome. Hamartomas are a histologically defined subtype of benign tumor and have established links to dysregulated mTOR activity. See Table 1.
The artisan would have had a reasonable expectation of success that stiripentol would provide LDHB inhibitory activity and that this inhibitor activity would aid in treatment of TSC, Peutz-Jegher’s syndrome, or PTEN-related hamartoma syndromes such as Crowden disease, BRRS, and proteus syndrome (i.e., diseases involving tumors and established links to dysregulated mTOR activity) because LDHB activity is pivotal in the tumorigenesis in cells with hyperactive mTOR signaling.
As indicated above, the claim limitation reciting that “the compound of formula (I) inhibits the mTOR pathway” defines the claimed method by a functional result of administering the compound which the prior art need not explicitly recognize or teach. A POSA would have reasonably expected that inhibiting LDHB using a known LDHB would functionally inhibit mTOR-mediated pathological signaling in diseases characterized by hyperactivation of the mTOR pathway (e.g., TSC, Peutz-Jegher’s syndrome, PTEN-related hamartoma syndromes such as Crowden disease, BRRS, and proteus syndrome (i.e., diseases involving tumors and established links to dysregulated mTOR activity)). The functional limitation is satisfied since a POSA would have reasonably expected the claimed functional result based on the teachings of the prior art.
Accordingly, the claimed invention as a whole would have been prima facie obvious to one of ordinary skill before the effective filing date of the claimed invention.
Response to arguments
Applicant argues that Inoki does not remedy Zha's and Okayama's deficiencies and, therefore, the combination of Zha, Okayama, and Inoki does not render any of the claims obvious. The alleged deficiencies do not exist as outlined in the response to Applicant’s arguments above.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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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/CHRIS E SIMMONS/Examiner, Art Unit 1629
/JAMES H ALSTRUM-ACEVEDO/
Supervisory Patent Examiner, Art Unit 1622