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. Acknowledgement is made of the receipt and entry of the claims filed on July 09, 2026
Action Summary
Claims 1-5, 9-11, and 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), and Glass et al (US2017/0020869 A1), are maintained.
Claims 1-5, 9-11, and 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), 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), are maintained.
It is noted the header of the rejection inadvertently identifies claims 1-5, 9-11, and 15 as being rejected. However, the body of the rejection expressly addresses claims 6, 7, 8, 12, 13, and 14. Accordingly, the maintained rejection set forth below corrects the header and clarifies the record.
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 remain 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 and claim 11, 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. Glass expressly identifies both FXS and PMS among the disorders contemplated for treatment and further teaches the use of pERK as a measure for assessing therapeutic efficacy, wherein a decrease in pERK indicates a reduction in severity of the disorder. Thus, Glass provides evidence that ERK-associated signaling was considered relevant to the therapeutic assessment of both disorders. 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.
Response to Arguments
Acknowledgement is made of the receipt and entry of Applicant’s arguments/remarks filed on July 09, 2026. Applicant’s arguments have been full considered but are not persuasive.
The rejection is maintained for the reasons set forth below. It is noted that the implication of Glass in the discussion of the summary section of the rejection has been clarified in response to Applicant’s arguments. Such clarification does not atter the basic trust or statutory basis of the rejection, not does it rely upon new prior art. Rather, the rejection continues to rely upon the same combination of references and the teachings thereof previously relied upon the prior Office Action.
Applicant argues that the combination of AMP Pharma, Snape, Phelan, and Glass fails to provide a motivation to administer AMO-01 to a subject having Phelan-MdDermid Syndrome (PMS) or a reasonable expectation of successfully treating PMS because the cited references allegedly fail to establish that PMS characterized by increased or aberrant Ras-ERK activation. Applicant further argues that because PMS is associated with deletion or disruption of SHANK3, inhibition of the Ras-ERK pathway would not have expected to provide a therapeutic effect in a subject having PMS.
In response, Applicant’s arguments are not persuasive because they construe the rejection as requiring a showing that increased Ras-ERK activation is established as the underlying cause of PMS. The rejection does not require such a finding. Rather, the ejection is based upon the collective teachings of the cited references and what those references and what those teachings would have suggested to one of ordinary skill in the art at the time of the invention.
AMO Pharma teaches AMO-01, the elected farnesyl dibenzodiazepinone compound, as an inhibitor of Ras-ERK intracellular pathway activation for treatment of Fragile X syndrome (FXS). Pheland teaches that PMS exhibits neurological manifestations overlapping those observed in FXS, including autistic-like behavior, speech delay, and development delay. Pheland further identifies FSX as part of the differential diagnosis of PMS and teaches that SHANK3 haploinsufficiency/disruption is associated with neurological manifestations of PMS.
Importantly, Glass provides more than a general disclosure concerning FXS. Glass expressly teaches a method of treating autism spectrum disorder and neurodevelopmental disorders and specifically identifies both Fragile X syndrome and Pheland McDermid syndrome among the disorders contemplated for treatment. Glass further teaches assessment of therapeutic efficacy by measurement of phosphorylated ERK (pERK) and/or phosphorylated AKT (pAKT), wherein a decrease in pERK or pAKT indicates a reduction severity of the disorder. Accordingly, the prior art expressly placed both FSX and MPS within a common therapeutic framework and identifies ERK-associated signaling as relevant to evaluating therapeutic efficacy.
Thus, one of ordinary skill in the art, considering AMO Pharma’s teaching that AMO-01 inhibits Ras-ERK pathway activation and is useful for treating FXS together with Pheland’s teachings concerning the clinical and neurological relationship between FSX and PMS and Glass’ express identification of both FSX and PMS as disorders susceptible to the disclosed therapeutic approach, would have had reason to administer AMO-01 to a subject having PMS with a reasonable expectation of obtaining a therapeutic benefit.
Contrary to Applicant’s argument, obviousness does not require the prior art to establish with certainty the precise biochemical mechanism by which AMO-01 would produce a therapeutic effect in PMS. Nor it is necessary to establish that increased Ras-ERK activation is the underlying cause of PMS. A reasonable expectation of success does not require absolute predictability or certainty of success; rather, the relevant inquiry is whether the ordinarily skilled artisan would have reasonably expected the proposed treatment to succeed based upon the teachings of the prior art as a whole.
Applicant’s argument concerning Shank3 also does not overcome the rejection. Applicant asserts that because functional Shank3 protein is “missing” in PMS, Shank3 is not present to be phosphorylated and inhibition of the Ras-ERK pathway therefore would not have been expected to have an effect. However, the cited Phelan reference teaches SHANK3 haploinsufficiency and disruption/deleting involving Shank3; such teaching does not establish that Shank3 protein is necessarily completely absent in every subject encompassed by the claims. Applicant therefore has not established that Shank3 -related teachings of the references would have taught one of ordinary skill way from the proposed treatment or otherwise negated the reasonable expectation arising from the combined prior-art teachings.
Furthermore, the claimed methods do not require treatment through any particular molecular mechanism, do not require establishing increased pERK in the subject before treatment, and do not require that AMO-01 exert its therapeutic effect through phosphorylation or dephosphorylation of Shank3. The claims require administration of the recited therapeutic context. Accordingly, Applicant’s arguments directed to whether a particular Ras-ERK/Shank3 mechanism has been conclusively established do not commensurately address the scope of the claimed method or the full basis of the rejection.
Applicant argues that Glass does not establish that PMS is characterized by increased or aberrant pERK and that the experiments concerning pERK in Glass are directed to FXS.
In response, Applicant’s argument is not persuasive. Even assuming arguendo that Glass does not expressly establish increase pERK as a characterization of PMS, Glass expressly identifies both FXS and PMS among the neurodevelopmental disorders contemplated for treatment and further teaches assessment of therapeutic efficacy by measurement of pERK or pAKT, wherein a decrease in either indicates a reduction in severity of the disorder. Thus, Applicant’s argument regarding Galss expressly demonstrates increased in pERK in PMS does not negate the remaining teachings of Glass or the collective teachings of the cited references upon which the rejection is based.
In particular, MAO Pharma teaches AMO-01 as a Ras-ERK pathway activation inhibitor for the treatment of FXS, Pheland teaches the recognized neurological and phenotypic similarities between FXS and PMS and identifies FXS in the differential diagnosis of Phelan-McDermid syndrome; and Glass expressly identifies both disorders as disorder contemplated for treatment and teaches pERK as a measure of therapeutic efficacy. Considered collectively, these teachings would have provided on of ordinary skill in the art with reason to administer AMO-1 to a subject having PMS with a reasonable expectation of obtaining therapeutic benefit.
Therefore, when the references are considered for everything they reasonably teach to one of ordinary skill in the art, the combination provides both a reason to administer AMO-01 to a subject having PMS and a reasonable expectation of obtaining therapeutic benefit. Applicant’s arguments do not overcome the prima facie case of obviousness. The rejection of claims 1-5, 9, 11, and 15 under 35 U.S.C. 103 is therefore maintained.
Claims 6, 7, 8, 12, 13, and 14 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.
Response to Arguments
Acknowledgement is made of the receipt and entry of Applicant’s arguments/remarks filed on July 09, 2026. Applicant’s arguments regarding claims 6-8 and 12-14 have been considered but are not persuasive.
Applicant argues that Ranger fails to cure the alleged deficiencies of AMO Pharma, Snape, Phelan, and Glass because Ranger does not teach treatment of PMS by inhibition of Ras-ERK activation.
In response this argument is not persuasive because Ranger is not relied upon to provide the reason for treating PMS with AMO-01. As discussed above, the combined teachings of AMP Pharma, Snape, Phelan, and Glass provide the reason to administer AMO-01 to a subject having PMS with a reasonable expectation of therapeutic benefit. Ranger is relied upon for the additional dosage and administration limitations recited in claims 6-8 and 12-14.
Ranger teaches administration of the same compound over therapeutically effective dosage ranges encompassing or overlapping the claimed ranges and further teaches slow injection of continuous injection over a period encompassing the claimed administration periods. Thus, once led by the primary combination to administer AMO-01 for PMS, one of ordinary skill in the art would have ha reason to employ the known therapeutically effective dosage and administration parameters taught by Ranger, including value falling within the claimed ranges, with a reasonable expectation of obtaining an effective administration regimen.
Applicant has not provided evidence establishing that the claimed dosage or infusion parameters produce an unexpected result relative to the overlapping prior-art ranges. Accordingly, Applicant’s argument that Ranger does not independently teach treatment of PMS does not address the purpose for which Ranger is relied upon and does not overcome the rejection. The rejection of claims 6-8 and 12-14 under 35 U.S.C. 103 is maintained.
Conclusion
Claims 1-15 are not 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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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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