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 .
Priority
This application is a continuation of U.S. Application Serial No. 16/759,436, filed on April 27, 2020, which is a national phase filing of International Patent Application No. PCT/IB2018/058345, filed on October 25, 2018, which claims the benefit of priority of U.S. Provisional Application Serial No. 62/577,821, filed on October 27, 2017.
Election/Restrictions
Applicant’s election of AMO-01 as the elected farnesyl dibenzodiazepinone compound in the reply filed on 12/13/2021 is acknowledged.
Claim Status
Claims 1-15 are pending and examined in accordance to the elected species.
Response to Arguments
Acknowledgement is made of the receipt and entry of Applicant’s arguments/remarks filed on October 21, 2025.
Applicant argument that the Examiner has failed to point to any relevant teachings on this point and therefore the skilled artisan would have lacked any reason to attempt treatment of PMS using an inhibitor of Ras-ERK is persuasive. Therefore, the rejection of claims 1-15 has been withdrawn.
Action Summary
Claims 1-15 rejected under 35 U.S.C. 103 as being unpatentable over AMO (Pharma Limited, June 07, 2016) in view of Snap et al (Presentation, Fragile X and Autism-Related Disorder, Gordon Research Conference, Mount Snow, West Dover, Vermont, June 7, 2016), Phelan (Mol Syndromol 2011;2:186-201), Gareth (PNAS, October 18, 2005, vol. 102, No. 42 pp. 15006-15011), and Ranger (US2006/0276436 A1), are withdrawn in light of Applicant’s argument.
Claim Rejections - 35 USC § 103
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 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 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 non-obviousness.
Claims 1-5, 9-11, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over AMO (Pharma Limited, June 07, 2016) in view of Snap et al (Presentation, Fragile X and Autism-Related Disorder, Gordon Research Conference, Mount Snow, West Dover, Vermont, June 7, 2016), Phelan (Mol Syndromol 2011;2:186-201), and Glass et al (US2017/0020869 A1).
AMO Pharma Limited suggests the use of AMO-1 as a Ras-ERK intracellular pathway activation inhibitor for the treatment of Fragile X syndrome (a common cause of autism), see first para. Moreover, AMO Pharma Limited teaches Fragile X syndrome is the most common cause of autism and symptoms of Fragile X syndrome include attention deficit and hyperactivity, anxiety, speech delay and seizures, see fifth para. AMO-1 is the same compound recited in claim 4, which falls within the scope of the formula (I) as evidenced by Figure 1 of Snape et al.
AMO Pharma Limited does not teach Phelan McDermid syndrome (PMS).
Phelan teaches the 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome, is a contiguous gene disorder resulting from deletion of the distal long arm of chromosome 22. In addition to normal growth and a constellation of minor dysmorphic features, this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia. In addition, more than 50% of patients show autism or autistic-like behavior, and therefore it can be classified as a syndromic form of autism spectrum disorders (ASD). The differential diagnosis includes Angelman syndrome, velocardiofacial syndrome, fragile X syndrome, and FG syndrome. Almost all of these deletions include the gene SHANK3 which encodes a scaffold protein in the postsynaptic densities of excitatory synapses, connecting membrane-bound receptors to the actin cytoskeleton. (See Abstract.) Moreover, Phelan teaches males with fragile X syndrome may have autistic-like behavior and speech delay in addition to developmental delay, similar to individuals with deletion of 22q13.3. Physical features of older males with fragile X syndrome, including tall stature, long face, and large ears, are similar to features seen in some males with 22q13.3 deletion syndrome. (See page 192, left column, second paragraph.) Phelan teaches haploinsufficiency for SHANK3 is responsible for the ASD symptoms seen in many patients with 22ql3.3 deletion syndrome. (See page 196, right column, first paragraph.) Phelan further suggests that disruption of SHANK3 may be responsible for at least some of the phenotypic features of 22q13.3 deletion syndrome. (See page 188, left column, second paragraph.)
Glass teaches a method for treating an autism spectrum disorder (ASD) or Neurodevelopmental Disorder (NDD) in a mammal suffering from such a disorder, comprising administering to the mammal, a pharmaceutically effective amount of a compound cyclic Glycyl-2-Allyl Proline (cG-2-AllylP), or cyclic cyclohexyl-G-2MeP, or cyclic cyclopentyl-G-2MeP to said mammal. (See claim 1.) Moreover, Glass teaches the disorder is selected from the group consisting of Autistic Disorder, Asperger Syndrome, Childhood Disintegrative Disorder and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), Pathological Demand Avoidance (PDA), Fragile X Syndrome (FXS), Angelman Syndrome, Tuberous Sclerosis Complex, Phelan McDermid Syndrome, Rett Syndrome, CDKL5 mutations, and X-Linked Infantile Spasm Disorder. (See claim 4.) Additionally, Glass teaches assessment of efficacy is via measurement of phosphorylated ERK (pERK) or phosphorylated Akt (pAkt) in lymphocytes of the mammal, where a decrease in either pERK or pAkt indicates reduction in severity of said disorder. (See claim 9.)
In sum, AMO Pharma Limited teaches AMO-1 (claimed elected compound) as a Ras-ERK intracellular pathway activation inhibitor for the treatment of Fragile X syndrome (a common cause of autism). Phelan teaches more than 50% of patients show autism or autistic-like behavior, and therefore it can be classified as a syndromic form of autism spectrum disorders (ASD) and the differential diagnosis includes fragile X syndrome. Phelan also suggests that disruption of SHANK3 may be responsible for at least some of the phenotypic features of 22q13.3 deletion syndrome. The teaching of a decrease in pERK indicating reduction in severity of disorders such as Fragile X Syndrome and Phelan McDermid syndrome with a compound cyclic Glycyl-2-Allyl Proline (cG-2-AllylP), or cyclic cyclohexyl-G-2MeP, or cyclic cyclopentyl-G-2MeP as taught by Glass implies increase of pERK in both Fragile X Syndrome and Phelan McDermid syndrome. One would reasonably expect inhibition of Ras-ERK intracellular pathway activation with AMO-1 to treat both Fragile X Syndrome and Phelan McDermid Syndrome.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the method taught by AMP Pharma Limited to treat autistic-like behavior and speech delay in Phelan McDermid syndrome and/or treat/inhibit Phelan McDermid syndrome to give Applicant’s claimed method. One would have been motivated by the fact that Phelan teaches fragile X syndrome is one of the diagnostic features of Phelan McDermid syndrome and the fact that fragile X syndrome share similar symptoms as Phelan McDermid syndrome, but also because Phelan teaches haploinsufficiency for SHANK3 is responsible for the ASD symptoms seen in many patients with 22ql3.3 deletion syndrome and because Glass teaches Fragile X Syndrome and Phelan McDermid syndrome can be treated by decreasing pERK indicating reduction in severity of the syndrome, implying both Fragile X Syndrome and Phelan McDermid syndrome cause an increase of pERK. One would reasonably expect AMO-1 having Ras-ERK activation inhibitory action for the treatment of autistic-like behavior and speech delay in fragile X syndrome to also successfully treat or inhibit Phelan McDermid syndrome via inhibition of the ERK activation.
Claims 1-5, 9-11, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over AMO (Pharma Limited, June 07, 2016) in view of Snap et al (Presentation, Fragile X and Autism-Related Disorder, Gordon Research Conference, Mount Snow, West Dover, Vermont, June 7, 2016), Phelan (Mol Syndromol 2011;2:186-201), and Glass et al (US2017/0020869 A1).as applied to claims 1-5, 9-11, and 15, in further view of Ranger (US2006/0276436 A1)
The teachings of AMO, Snapm Phelan, and Glass have been discussed in the above rejection.
AMO, Snapm Phelan, and Glass collectively do not teach the therapeutically effective amount of the at least one farnesyl dibenzodiazepinone compound is between 80 and 160 mg/m2, delivered to the subject over 4-8 hours as claimed in claims 7, 8, 13, and 14. Moreover, AMO, Snapm Phelan, and Glass collectively do not teach the effective amount of the compound is between 0.1µg/kg and 200 mg/kg as claimed in claims 6 and 12.
Ranger does not specifically teach the therapeutically effective amount of the at least one farnesyl dibenzodiazepinone compound is between 80 and 160 mg/m2, delivered to the subject over 4-8 hours. However, Ranger et al. teaches when administered by continuous intravenous infusion (CIV), the therapeutically effective amount ranges from about 10 mg/m2/day to about 1000 mg/m2/day, from about 20 mg/m2/day to about 750 mg/m2/day, from about 30 mg/m2/day to about 500 mg/m2/day, or about 120 mg/m2/day to about 480 mg/m2/day, see para [0150]. Ranger et al. further teaches the effective dose can be administered either as a single administration event (e.g., oral, topical or intranasal administration or bolus parenteral injection) or as a slow injection or continuous infusion, e.g., over 30 minutes to about 24 hours, see para [0153]. Moreover, Ranger et al. teaches continuous intravenous (CIV) administration of formulation D11 consisting of polysorbate 80, PEG-400, ethanol, saline, dextrose, and 25-75 mg/kg /day per body weight of compound 1 in healthy subject, see Example 11 and Table 4. Ranger does not disclose the exact claimed values, but does overlap: in such instances even, a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the therapeutic dose recited claims 6. 7, 8, 12, 13, and 14 with the expectation of producing acceptable pharmacokinetics and toxicity as taught by Ranger et al. since Ranger et al. teaches administration of compound 1 (claimed compound) in a formulation comprising a pharmaceutically acceptable excipient or diluent in a healthy subject produced acceptable pharmacokinetics.
Conclusion
Claims 1-15 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628