Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 26-48 are under examination in the instant office action.
Claim Rejections - 35 USC § 112-Scope of Enablement
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 26-48 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 how to make instant compounds as in instant claims, does not reasonably provide enablement for treating a subject suffering from Smith-Lemli-Opitz Syndrome. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to how to use the invention commensurate in scope with these claims.
The enablement rejection is focusing on how the compounds described in claims 26-48 are used for treating a Smith-Lemli-Opitz syndrome in a human population that includes infants.
In this regard, the application disclosure and claims have been compared per the factors indicated in the decision In re Wands, 8 USPQ2d 1400 (Fed. Cir., 1988) as to undue experimentation. The factors include:
1) the nature of the invention;
2) the breadth of the claims;
3) the predictability or unpredictability of the art;
4) the amount of direction or guidance presented;
5) the presence or absence of working examples;
6) the quantity of experimentation necessary;
7) the state of the prior art; and,
8) the relative skill of those skilled in the art.
The relevant factors are addressed below in the basis of comparison of the disclosure, the claims, and the state of the prior art in the assessment of undue experimentation.
Note that the specification must be enabling as of the filing date. MPEP §2164.05(a). In the instant case, the filing date is October 7, 2014, the date of U.S. Provisional Application No. 62/060,932.
As set forth in In re Marzocchi et al., 169 USPQ 367 (CCPA 1971):
"[A] [s]pecification disclosure which contains the teachings of manner and process of making and using the invention in terms corresponding to the scope to those used in describing and defining subject matter sought to be patented must be taken as in compliance with the enabling requirements of first paragraph of 35 U.S.C. 112, unless there is reason to doubt the objective truth of statements contained therein which must be relied on for enabling support; assuming that sufficient reasons for such doubt exists, a rejection for failure to teach how to make and/or use will be proper on that basis, such a rejection can be overcome by suitable proofs that teaching contained in the specification is truly enabling."
Applicant’s invention is directed to a method of treating a subject suffering from Smith-Lemli-Opitz Syndrome (SLOS) comprising administering to a subject an effective amount of compounds as in instant claim 26 or pharmaceutically acceptable salts thereof. Applicant’s and the state of the art demonstrate how to make a genus of compound having a core cholesterol structure and compounds in claim 26 [entire specification].
Although the prior art of Upasani et al. (WO2013036835 A1; of record) shows that compounds of formula I are considered to have NMDA modulating activity. Upasani et al. teaches 3-α and β-hydroxy steroids with the potential of NMDA receptor modulators [0007]. The compounds are useful for preventing and/or treating autism spectrum disorder (ASD), or autism among other CNS- related conditions [0007]. The compounds are expected to show improved in vivo potency, pharmacokinetics properties, oral bioavailability and stability [0007]. The compounds have the following formula I and I(w)
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or pharmaceutical acceptable salt and
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L1 and L2 are selected from a group consisting of a bond, a substituted or unsubstituted C1–C6 alkylene, a substituted or unsubstituted C2-C6 alkenylene, substituted or unsubstituted C2-C6 alkynylene, a substituted or unsubstituted hetero C1-C6 alkylene, a substituted or unsubstituted hetero C2-C6 alkenylene, and a substituted or unsubstituted hetero C2-C6 alkynylene;
L3 is a substituted or unsubstituted C1–C6 alkylene, a substituted or unsubstituted C2-C6 alkenylene, substituted or unsubstituted C2-C6 alkynylene, a substituted or unsubstituted hetero C1-C6 alkylene, a substituted or unsubstituted hetero C2-C6 alkenylene, or a substituted or unsubstituted hetero C2-C6 alkynylene;
each instance of X and X is independently -O-, -S-, or -NH-;
R1 is hydrogen or substituted or unsubstituted alkyl;
R3b is hydrogen;
R3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
each instance of R2, R11a, and R11b is independently hydrogen or -ORB1, wherein RB1 is hydrogen or substituted or unsubstituted alkyl,
each of R6a and R6b is independently hydrogen, halo, or substituted or unsubstituted alkyl, and represents a single or double bond, provided if a double bond is present, then one of R6a or R6b is absent, and provided if a single bond is present, then the hydrogen at C5 is in the alpha or beta position;
each instance of R19 and R20 is independently hydrogen or –CH3;and each instance of R23a and R23b is independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R23a and R23b are joined together to form substituted or unsubstituted C3-C6 cycloalkyl;
R24 is hydrogen or substituted or unsubstituted alkyl;
Y is -O-, -S-, or -NRZ5-;
RZ4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR25, -SRZ5, or -N(RZ5)2;
each instance of RZ5 is independently hydrogen or substituted or unsubstituted alkyl; and
each instance of Rz6 is independently hydrogen or substituted or unsubstituted alkyl, or two Rz6 groups are joined to form a C3-6 carbocyclic ring; and the subscript n is 0 or 1 [0008]. Further, describes a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) [00107]. The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents [00314]. The compounds were incubated in a concentration of 1 µM [00454]. Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient [00299].
The prior art of Upasani et al. identifies compounds of formula I having a NMDA modulating receptor activity. The art shows that not all NMDA modulating receptors have the same therapeutic effect in patient, activity and many vary structurally. For example, Tomek et al. Pharmaceuticals (Basel), Feb 2013, 6(2):251-258; of record) teaches several NMDA receptor modulators Memantine, and Acamprosate are considered NMDA receptor antagonist while D-cycloserine is an NMDA partial agonist. Thus, Tomek et al. demonstrates the general description of NMDA receptor modulating compound can have two different activities (e.g., antagonistic or agonistic). Therefore, the art shows that the activity of a single NMDA modulating receptor is not representative of the entire genus and Applicant has not identified the activity of compounds in claim 26.
Svoboda et al. (Am J Med Genet C Semin Med Genet (2012), pp.285-294; of record) teaches Smith-Lemli-Opitz syndrome is an autosomal recessive genetic condition with a broad phenotype that results from deficiency of the final enzyme of the cholesterol synthesis pathway [p.2, para. 1]. The syndrome is characterized by multiple, variable and minor malformation and intellectual disability [p.2, para. 1]. The most common therapies being studied or applied clinically include dietary cholesterol supplementation and 3-hydroxy-3-methylglytaryl coenzyme A reductase inhibitors (HMG CoA) reductase inhibitors, also known as statins). The therapeutic goal for the treatment of SLOS has been enhance cholesterol production and/or accretion, and to decrease the accumulation of potentially toxic cholesterol precursors such as 7-hydroxycholesterol (7DHC) and 8-hydroxycholesterol (8DHC) [p.2, para. 2]. Clinical goals of treatment largely focus on improved development and behaviors such as irritability, hyperactivity, self-injurious behavior and sleep difficulties, but also improved linear growth and weight gain [p.2, para. 2].
Simvastatin is a HMG-CoA reductase inhibitor that inhibits cholesterol pathway proximal to the enzymatic defect in SLOS [p.4, para 3]. One study shows a side in plasma cholesterol level and a decrease in the 7DHC/Cholesterol ratio with use of simvastatin without cholesterol supplementation [p.4, para. 4]. Improvement in anthropometric measurements, including length, weight, and head circumference were also observed [p.5, para. 1].
Other types of treatment include bile acid and downstream hormone supplementation, surgical intervention, anesthesia and supportive care [p.5, para4-5]. Other aspects of the syndrome such as behavioral modification may be treated with certain antipsychotic drugs [p.6, para. 5]. Future therapies include antioxidants, prenatal cholesterol supplementation and gene therapy [p.7, para. 2].
Given the activities of compounds in claim 26 is not clearly identified, it would have been premature to extrapolate that the compound was useful in the treatment of SLOS, one of ordinary skill in the art would not be able to predict that compounds in claim 26 would be able to treat SLOS a multiple complex syndrome including all of the aspects and symptoms associated with SLOS. The artisan would have required sufficient direction as to how, at minimum, the compounds in claim 26 could be effective in the treatment of SLOS by enhancing cholesterol production and/ or accretion or being able to improved development and behaviors in the subject. Since the activity of compounds in claim 26 is not clearly identified by Applicant. Such that the artisan would have been imbued with at least a reasonable expectation of success in treating SLOS. The state of the prior art of Upasani et al. shows structurally similar compounds and attribute the compounds to be NMDA modulators. Further, Svoboda et al. demonstrates the difficulties encounter in developing new therapies for SLOS and treating SLOS.
To the artisan, the concept of single agent effective to treat SLOS would not have been considered representative or suggestive of the same efficacy in the treatment of all the symptoms associated with SLOS in the absence of any evidence or reasoning to do so. Additionally, since the skilled artisan would have expected the interaction of a particular agent in the treatment of SLOS in a patient population to be specific (accordingly to the severity of the disease and age of the patient), and highly unpredictable absent to a clear understanding of the activity and biochemical mechanism of the compound, one of skill in the art would have no other recourse but undue experimentation to undertake extensive testing to determine whether one single compound is capable of treating all the aspect and symptoms of SLOS.
MPEP §2164.03 states, "The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The 'amount of guidance or direction' refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004)...In applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required."
"Nascent technology…must be enabled with a 'specific and useful teaching'. The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004). See MPEP §2164.03.
As established supra, the method for treating a subject suffering from SLOS comprising administering to the subject an effective amount of a compound in claim 26 was unpredictable at the time of the invention, given that the art recognized the complexity of SLOS, the art clearly lacked information in regards to how to treat effectively SLOS with compounds as in instant claim 26 given the complexity of the disease. Thus, the method of treatment of the invention must be considered nascent, since the state of the art at the time of the effective filing date did not recognize the claimed objective could be accomplished with any reasonable expectation of success. As a result, the amount of guidance required from Applicant necessarily is high, since Applicant cannot rely upon what is known in the art about the nature of the invention for such guidance.
In the as-filed specification, Applicant describes a genus of compounds including the compounds in claim 26 has having NMDA modulating activity. However, Applicant fails to demonstrate whether the modulating activity was agonistic or antagonistic and or any IC50 values would have been capable of treating SLOS. Further, Applicant does not provide any evidence that compounds in claim 26 or any the compounds describe in the as-filed specification would have been effective in treating SLOS. Applicant has also failed to provide any evidence, or describe any protocol, that addresses treating SLOS in such that one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success in treating SLOS with the claimed compound based on the direction provided in the present specification and the state of the prior art.
The quantity of experimentation to use a compound in claim 26 in the treatment of SLOS encompassed by the claims would be an undue burden to one of ordinary skill in the medicinal, biological and pharmacological art, since the skilled artisan is given inadequate guidance for the reasons stated above. Even with undue burden of experimentation, there is not a reasonable expectation of success that one would be able to treat SLOS with the compounds in claims 26-48 in the manner claimed in view of what was known in the prior art, as evidenced by the teachings of Upasani et al., Tomek et al. and Svoboda et al. Since the references disclosed the complexity of SLOS and the different aspects require for the treatment depends on sex, age and severity of the disease which in turn dictates the choice of therapy employed during treatment. While the lack of working examples cannot be the sole factor in determining enablement, the absence of substantial evidence commensurate in scope with the breadth of the presently claimed subject matter, in light of the unpredictable nature of the art and the absence of direction from Applicant, provides additional weight to the present conclusion of insufficient enablement in consideration of the Wands factors as a whole.
The basis for the present rejection is not simply that experimentation would be required, since it is clear from the state of pharmaceutical, medical and chemical arts that experimentation in this art is not all uncommon, but that the level of experimentation required in order to practice these aspects of the invention in the absence of adequate enabling direction by Applicant would be undue. See In re Angstadt, 537 F.2d 498, 190 USPQ 214, 219 (CCPA 1976), which states, "The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.”
In view of the discussion of each of the preceding seven factors, the level of skill in the art is high and is at least that of a medicinal chemist or organic chemist with several years of experience in the art.
As the cited art and discussion of the above factors establish, the disclosure and supporting examples provided in the present specification, coupled with the state of the art at the time of the invention, fail to imbue the skilled artisan with a reasonable expectation or ability to use the full scope of the invention as instantly claimed. In order to actually use the claimed invention, it is clear from the discussion above that the skilled artisan could not rely upon Applicant’s disclosure as required by 35 U.S.C. 112(a) in order to practice the full scope of embodiments presently claimed.
Applicant does not seem to be enable to treat SLOS with compounds in claims 26-48.
Conclusion
Claims 26-48 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHOBHA KANTAMNENI, Ph.D whose telephone number is (571)272-6013. The examiner can normally be reached on Monday-Friday 8am-4pm.
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/SHOBHA KANTAMNENI/Primary Examiner, Art Unit 1627