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 .
Claims 1, 39, 49-51, 53-55, 57-60, 62, 67, 74, 78, 80, 81, 83, 84, 86, 88, 89, 91, 92, 95, 97, 103, 106-108, and 111, submitted on 13 March 2024, represent all claims currently under consideration.
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 (i.e., changing from AIA to pre-AIA ) 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.
Priority
This application is a 371 of PCT/US2022/020039, filed 11 March 2022, which claims priority to provisional US 63/185,466, filed 7 May 2021, and provisional US 63/160,413, filed 12 March 2021. The effective filing date is 12 March 2021.
Information Disclosure Statement
One Information Disclosure Statement (IDS), submitted on 9 August 2024, is acknowledged and has been considered.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 39, 49-51, 53-55, 57-60, 62, 67, 74, 78, 80, 81, 83, 84, 86, 88, 89, 91, 92, 95, 97, 103, 106-108, and 111 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1 is indefinite because the claim recites that the compound is a compound of the provided formula, (bitopertin), or a salt or thereof. The structure provided is of bitopertin, so the Applicant is being redundant in reciting both the structure and the name. At the same time, the structure and name are written in a list to make it appear as though they are separate and unique species. Claims 39, 49-51, 53-55, 57-60, 62, 67, 74, 78, 80, 81, 83, 84, 86, 88, 89, 91, 92, 95, 97, 103, 106-108, and 111 are similarly rejected as indefinite for depending upon an indefinite claim without resolving the underlying issue of indefiniteness.
Allowable Subject Matter
Claims 1, 39, 49-51, 53-55, 57-60, 62, 67, 74, 78, 80, 81, 83, 84, 86, 88, 89, 91, 92, 95, 97, 103, 106-108, and 111 would be allowable if rewritten or amended to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action.
The following is a statement of reasons for the indication of allowable subject matter: Matte (JCI Insight, 14, 4(22) (See IDS, 9 August 2024) teaches the treatment of β-thalassemia using the GlyT1 inhibitor bitopertin. Sornjai (International Journal of Biological Macromolecules, Volume 94, Part A, 2017) (See IDS, 9 August 2024) teaches that β-thalassemia is associated with ribosomal biogenesis dysfunction, associated with haploinsufficiency at 28S. The artisan would not be motivated, nor would they have a reasonable expectation of success in, using bitopertin for the treatment of this form of anemia as the data presented by Matte only demonstrate the treatment of β-thalassemia, a different form of anemia, and there is no teaching, suggestion, or motivation found to apply this treatment to Diamond-Blackfan anemia. Farrar (Blood, 2011 Nov 1; 118 (26)) discusses ribosomal protein mutations found in Diamond-Blackfan anemia, and states that perturbations of the ribosome appear to be critically important in DBA and identified deletions at known DBA-related ribosomal protein gene loci in 17% (9 of 51) of patients without an identifiable mutation, including RPS19, RPS17, RPS26, and RPL35A. Sieff (DBA Syndrome, 2009 Jun 25, GeneReviews) provides a more detailed overview of the mutations present in Diamond-Blackfan anemia. Table 1 (Page 5) lists the mutations commonly seen in DBA, and shows that mutations in RPS28 are incredibly rare. Quarello (British Journal of Hematology, Volume 172, Issue 5, 2016) provides an overview of ribosomal RNA in Diamond-Blackfan anemia, and shows that 15 genes are known to be mutated (RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPS27, RPS29, RPL5, RPL11, RPL15, RPL26, RPL27, RPL31, RPL35A) (Introduction). Thus, at the time of filing of the examined application, there was no indication of the involvement of ribosomal protein S28 in Diamond-Blackfan anemia, and thus there would be no reasonable expectation of success in applying bitopertin for the treatment of this specific form of anemia. The closest art comes from Winter (Experimental Hematology, Volume 44, Issue 10, October 2016, 964-974) and Yang (Science Translational Medicine, Volume 8, No. 338, 11 May 2016) (See IDS, 9 August 2024). Winter investigated the effects of inhibition of GlyT1 using bitopertin on erythropoiesis and iron homeostasis in rats. GlyT1 inhibition significantly affected erythroid heme biosynthesis, manifesting as microcytic hypochromic regenerative anemia with a 20% steady-state reduction in hemoglobin. The study concludes by stating that an imbalanced heme–globin interregulation leading to excess of either free heme or globin chains is the well-established pathogenesis of a broad spectrum of hematological diseases such as beta-thalassemia or erythropoietic porphyria. Delayed globin transcription with an associated excess of free heme has been identified recently in bone marrow culture systems from patients with Diamond-Blackfan anemia and del(5) myelodysplastic syndrome as the causal reason for the ineffective erythropoiesis. Those studies also provided experimental evidence that inhibition of heme synthesis could improve erythroblast survival. The selective inhibition of heme biosynthesis with an undisturbed systemic iron homeostasis by targeting GlyT1 might provide a promising therapeutic concept for such disorders (Conclusions). Yang cultured bone marrow cells from Diamond-Blackfan anemia patient and determined how heme and globin are coordinated. The authors showed that globin translation initiates slowly, whereas heme synthesis proceeds normally. This results in insufficient globin protein, excess heme and excess reactive oxygen species in early erythroid precursors, and CFU-E (colony-forming unit–erythroid)/proerythroblast cell death. The cells that can more rapidly and effectively export heme or can slow heme synthesis preferentially survive and appropriately mature. Consistent with these observations, treatment with 10 mM succinylacetone, a specific inhibitor of heme synthesis, improved the erythroid cell output of DBA marrow cultures by 68 to 95%, whereas erythroid cell output of concurrent control marrow cultures decreased by 4 to 13%. The studies demonstrate that erythropoiesis fails when heme exceeds globin. The data further suggest that therapies that decrease heme synthesis (or facilitate heme export) could improve the red blood cell production of persons with DBA (Abstract). However, there is no teaching, suggestion, or motivation to combine these teachings, as Yang uses a compound which is distinct and acts through a different mechanism from bitopertin, and Winter provides no specific data which demonstrates that bitopertin would be effective in treating DBA, rather postulating that this method could be effective.
Conclusion
Claims 1, 39, 49-51, 53-55, 57-60, 62, 67, 74, 78, 80, 81, 83, 84, 86, 88, 89, 91, 92, 95, 97, 103, 106-108, and 111 are rejected.
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/P.M.R./ Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625