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
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 13 January 2026 has been entered.
Applicant’s amendment of 13 January 2026, in which claims 1, 7, 13, 16, 17 have been amended, claims 14-15, 18-22 have been cancelled, and new claims 23-29 have been added, is acknowledged.
Claims 1, 3-10, 12-13, 16-17, 23-29 are pending in the instant application.
Claims 1, 3-10, 12-13, 16-17, 23-29 are being examined on their merits herein.
Response to arguments of 13 January 2026
In view of Applicant’s amendment of 13 January 2026, all the rejections to claims 14-15, 18-22 are herein withdrawn. Claims 14-15, 18-22 have been cancelled.
In view of Applicant’s amendment of 13 January 2026, the rejection of claims 1, 3-10, 12 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description/new matter, is herein withdrawn. Applicant has deleted new matter from independent claim 1.
In view of Applicant’s amendment of 13 January 2026, the rejection of claims 1, 3-10, 12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is herein withdrawn. Applicant has removed from claim 1 the term “low level of HbF” and the term “rapidly metabolized and excreted”.
In view of Applicant’s amendment of 13 January 2026, the rejection of claims 14-22 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is herein withdrawn. New rejections are made below, based on Applicant’s amendment of 13 January 2026.
In view of Applicant’s amendment of 13 January 2026, the rejection of claim 13 under 35 U.S.C. 102(a)(1) over Oseghale; and the rejection of claim 13 under 35 U.S.C. 102(a)(1) and 102 (a)(2) over Rephaeli, are herein withdrawn. Applicant has amended claim 13 to recite a pharmaceutical composition comprising AN-233 and hydroxyurea. New rejections are made below, based on Applicant’s amendment of 13 January 2026.
In view of Applicant’s amendment of 13 January 2026, the rejection of claims 1, 5 under 35 U.S.C. 103 over Oseghale, is herein withdrawn. Applicant has deleted from independent claim 1 the limitation that AN-233 is administered orally, locally or subcutaneously. A new/modified rejection is made below, based on Applicant’s amendment of 13 January 2026.
Regarding rejections made over Oseghale, the reference by Oseghale has 9 co-authors, 3 of which are co-inventors of the instant application. A Declaration under 37 CFR 1.132 (see final rejection mailed on 13 August 2025) is insufficient to overcome a rejection over Oseghale; rather, Applicant is to submit a Declaration under 37 C.F.R. 1.130(a) showing that the subject matter disclosed in the reference by Oseghale was obtained directly or indirectly from the inventor or a joint inventor of this application, and is therefore not prior art under 35 U.S.C. 102(a)(1).
Applicant writes (Response of 13 January 2026, page 9, 4th paragraph) that the Declaration “is expected to be submitted shortly”.
Applicant also writes (page 9, second and third paragraph) that “the claims are novel over Oseghale; the examiner has tacitly acknowledged the foregoing […]”. These statements are misrepresentations of what the examiner has indicated in the final rejection of 13 August 2025.
In the absence of a Declaration under 37 C.F.R. 1.130(a), new and modified rejections are being made over Oseghale, based on Applicant’s amendment of 13 January 2026.
Applicant’s arguments (Remarks of 13 January 2026, pages 10-19) against the rejection of claims 1, 3-9, 12-22 under 35 U.S.C. 103 over Rephaeli, in view of Atweh, have been considered.
Applicant argues (page 11-12) results in treating anemia with AN-233 (Rephaeli) are not predictive of results in treating SCD.
Applicant refers to the Declaration under 37 CFR 1.132, signed by Dr. Betty Pace, co-inventor, submitted on 7 May 2025, which had been carefully considered in the final rejection of 13 August 2025.
Applicant argues (page 12, last paragraph-page 13) that the art teaches away from assuming anemia treatments apply to hemoglobinopathies. Applicant argues (page 13) that supplementing an anemic subject with iron is a typical method of treating anemia; yet, supplementing a patient diagnosed with a hemoglobinopathy with iron does not result in effective treatment; and iron has been associated with worsening conditions of sickle cell disease. Thus, Applicant has shown that other drugs known to treat anemia are ineffective to treat SCD/thalassemia.
Applicant argues (page 13, last two lines-page 14) no reasonable expectation of success in treating SCD with AN-233.
Applicant argues (page 14) that neither Rephaeli nor Atweh teach the effect ALA has on gamma-globin and HbF production, and that Rephaeli does not teach which type of hemoglobin is increased, and there was no reason to believe that AN-233 would selectively increase HbF.
In response, the rejection is made over the combined teachings of Rephaeli and Atweh.
Rephaeli teaches that AN-233 is a butyrate prodrug, and Atweh teaches that butyrate is an HbF (fetal hemoglobin) -inducing agent in patients with sickle cell disease (SCD) and beta-thalassemia. Atweh teaches that other butyrate prodrugs namely arginine butyrate or sodium phenylbutyrate are effective to increase HbF levels in patients with SCD. Thus, the person of ordinary skill in the art would have administered AN-233 to a subject suffering from a hemoglobinopathy with the expectation that, upon administration, AN-233 will be converted in vivo into butyrate, which is effective to treat said hemoglobinopathy.
Applicant argues (pages 15-17) that AN-233 treatment of hemoglobinopathies is unexpectedly good.
Applicant refers to a literature reference by Liu, provided in Appendix E of the Declaration submitted on 05/07/2025, and argues that the effect ALA has on gamma-globin and HbF production was first demonstrated in Fig.1A-1D by Liu.
Applicant argues that Liu shows that ALA is effective to increase HbF levels in erythroid cells (Figure 1D).
Applicant then argues (page 16, last paragraph, page 17) that Figure 1C in the instant application shows that the population of cells positive for HbF (F-cells) increased from 10% in cells treated with vehicle control (EtOH) to approx. 19% with administration of 0.125 mM AN-233, while the F-cell population in cells treated with butyrate (BA) alone 0.125 mM, or with ALA alone 0.125 mM, remained unchanged compared to EtOH vehicle control. Applicant argues (page 17) that Applicant achieves a synergistic effect in increasing F-cell populations with AN-233, which is unexpected.
The examiner acknowledges Figure 1C, yet the examiner requests that Applicant explains the link between the number of F-cells, or rather the %F-cells (from total Hb cells?) in an in vitro assay and efficacy in a method of treating a hemoglobinopathy disorder, such as SCD or beta thalassemia, in a subject in need thereof, as claimed. The examiner has previously acknowledged (final rejection of 08/13/2025) all the data presented in support of AN-233, alone and in combination with HU, being effective in treating SCD and thalassemia (Declaration of 05/07/2025). The question is how and why is Figure 1C (in vitro assay) relevant to the instant claims; how does an increase in %F-cell translate into efficacy in vivo in a method of treating a hemoglobinopathy.
Applicant argues (pages 17, last paragraph-18) that efficacy by oral administration was unexpected. Applicant argues that Atweh expresses concerns about the bioavailability of butyrate prodrugs, and Applicant were the first to demonstrate effective oral administration of AN-233 with 7-fold increase in F-cell population. In response, regarding the bioavailability achieved with AN-233 (the examiner also notes PK studies, the statement at point 14 Declaration that AN-233 provides a treatment with a longer half-life than butyrate treatment alone, and the better PK of AN-233 compared to butyrate (which shows accelerated excretion, point 18, Declaration)), it is noted that AN-233 was known at the time of the invention, and its bioavailability and PK properties (longer half-life, less rapidly metabolized than butyrate) are inherent to AN-233.
The examiner noted (final rejection) that AN-233 is a dual/mutual prodrug, in which two different drugs, butyrate and ALA, acting via different mechanisms to treat SCD, are covalently linked.
Regarding the establishment of unexpected results, a few notable principles are well settled. It is applicant’s burden to explain any proffered data and establish how any results therein should be taken to be unexpected and significant. See MPEP 716.02 (b). The claims must be commensurate in the scope with any evidence of unexpected results. See MPEP 716.02 (d). Further, A DECLARATION UNDER 37 CFR 1.132 must compare the claimed subject matter with the closest prior art in order to be effective to rebut a prima facie case of obviousness. See, MPEP 716.02 (e). In this case, regarding method claims 1, 3-10, 12, 29, should Applicant present data (for example, data in an in vitro assay relevant to the disease (SCD) treated) in support of some unexpectedly better/ synergistic results in treating SCD/thalassemia or retinopathy (claim 29) caused by SCD with dual prodrug AN-233, compared to butyrate alone, and compared to ALA alone, such data will be considered and may advance prosecution. See also request above to explain Figure 1C and its relevance.
Regarding composition claims 13, 16-17, 23, 26, should Applicant present data in support of some unexpectedly better (synergistic, not additive) results with a combination of AN-233 and HU, compared to AN-233 alone and HU alone, such data will be considered and may advance prosecution.
Regarding method claim 28, should Applicant present data in support of some unexpectedly better (synergistic, not additive) results in treating a hemoglobinopathy disorder with a combination of AN-233 and HU, compared to AN-233 alone and HU alone, such data will be considered and may advance prosecution.
For all the reasons above, the rejection of the claims is herein maintained, and modified rejections are made below, based on Applicant’s amendment of 13 January 2026.
Applicant’s arguments (page 19) against the rejection of claims 1, 8-10 under 35 U.S.C. 103 over Rephaeli, in view of Atweh, in further view of Yahouedehou, are centered on arguments presented above. For the same reasons as above, this rejection is herein maintained.
Applicant argues (Remarks of 13 January 2026, page 19, last paragraph, page 20) against the rejection of the instant claims on the ground of nonstatutory double patenting over claims 8-17 of U.S. Patent No. 9,018,257, in view of Atweh. Applicant argues that instant claims 1, 3-9, 12 are drawn to methods, while reference claims are drawn to compositions. In response, it is proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010). MPEP 804.II.B.1 (Construing the claim using the reference patent or application disclosure).
Further, MPEP 804.II.B.1 states: In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02.
In this case, the claims of reference patent U.S. Patent No. 9,018,257 are drawn to a compound of formula (I) or a pharmaceutical composition thereof; the genus of compounds of formula (I) encompasses the instant compound AN-233. Further, compound (C) in claim 14 of U.S. Patent No. 9,018,257 is a direct structural homolog ethyl vs. methyl of AN-233.
The Specification of U.S. Patent No. 9,018,257 teaches that the co-drugs of formula (I) are hydrolyzed in vivo to one or more active compounds, such as 5-ALA and a carboxylic acid compound (butyric acid) that is active as an HDAC inhibitor.
The person of ordinary skill in the art would have administered 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) to a subject suffering from a hemoglobinopathy such as sickle cell disease, or sickle cell anemia or beta-thalassemia, because claims 8-17 of U.S. Patent No. 9,018,257 teaches that a compound of formula (I) such as 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) is a butyrate prodrug (AN-233 is hydrolyzed in vivo to butyric acid, which is active as an HDAC inhibitor), and Atweh teaches that butyrate, other butyrate prodrugs are effective to treat a hemoglobinopathy such as SCD or thalassemia. Thus, the person of ordinary skill in the art would have administered 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) to a subject suffering from a hemoglobinopathy with the expectation that, upon administration, AN-233 will be converted in vivo into butyrate, which is effective to treat said hemoglobinopathy.
This rejection is herein maintained, and a modified rejection is made below, based on Applicant’s amendment of 13 January 2026.
Applicant’s amendment of 13 January 2026 necessitated the following new and modified rejections.
Claim Rejections- 35 USC 112
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 13, 16, 17, 23, 24, 28 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.
Independent claim 13, as amended, is drawn to a pharmaceutical composition comprising an effective amount of AN-233 and hydroxyurea to increase the percentage of HbF positive cells (F-cells) in a subject in need thereof. Claim 13, and dependent claims 17, 23 are indefinite because it is unclear what is meant by “an effective amount of AN-233 and hydroxyurea to increase the percentage of HbF positive cells (F-cells) in a subject in need thereof.”
Claims 13, 16, 17, 23, 24 are interpreted to be product claims.
Claim 13 recites “an effective amount […] to increase the percentage”, yet it is unclear what the effective amount is, how the increase is measured, and in what sample; further, the term “percentage” refers to a ratio between HbF cells and a total number without defining what the total number is. It is unclear how the increase is to be measured, as the claim fails to establish a standard or threshold level. It is unclear how the increase is measured, and in what biological sample. It is further unclear how is the percentage calculated, because it is unclear what is the total number used to calculate the percentage of F-cells. In other words, it appears that claim 13 and dependent claims are directed towards measuring levels of biological molecules in two different biological samples and comparing said levels between the two different biological samples; however, the claims fail to clearly establish the origins of the two different biological samples, or the reference or standard by which one would make a comparison of levels of the one or more biological molecules. One wishing to practice the instantly claimed invention would thus not recognize the metes and bounds for which Applicant seeks protection.
It is unclear what is “an effective amount” in claim 13. The test is whether one skilled in the art could determine specific values for the amount based on the disclosure. The Specification teaches [00031] Figures 5A-5D show that AN-233 increases HbF expression in b-YAC transgenic mice. In Figure 5A 5-6 months old b -YAC transgenic mice were treated with 200 or 300 mg/kg of AN-233 dissolved in water for 4 weeks by intraperitoneal injections; water (vehicle) and hydroxyurea (HU) treatments were completed as controls to assess the in vivo effect of AN-233(N= 5 per group; 3 males and 2 females). In Figure 5B blood samples were collected at week 0, 2 and 4 were stained with acridine orange for reticulocyte percent by flow cytometry. In Figure 5C peripheral blood was stained with FITC-conjugated anti-HbF antibody and flow cytometry performed to quantify the F-cells by FlowJoTM data analysis. In Figure 5D the level of HbF expression was measured by MFI data generated by flow cytometry analysis.
PNG
media_image1.png
394
612
media_image1.png
Greyscale
There is no data showing an increase % of F-cells with a combination of AN-233 and HU (only with AU-233 alone and with HU alone, Fig. 5C), as recited in instant claim 13, and there is no indication what is actually an amount of a combination of AN-233 and HU “effective to increase % of F-cells in a subject in need thereof”. Thus, based on the disclosure, a POSITA cannot determine what an effective amount of a combination of AN-233 and HU “to increase % of F-cells in a subject in need thereof” is.
Claim 16 is drawn to the composition of claim 13, wherein the amount of the combination is effective to, when administered to a subject, (i) lower OCTN1 expression; and/or
(ii) additively induce fetal hemoglobin in the subject’s red blood cells when compared to treatment with hydroxyurea alone.
Claim 16 is unclear because it depends on claim 13 and recites “the combination”; yet, claim 13 does not recite a combination [of AN-233 and HU]. As such, there is insufficient antecedent basis for the term “the combination” of claim 16, in claim 13.
Further, it is unclear what is an amount “effective” in claim 16 to lower OCTN1 expression- it is unclear what this effective amount is, how the decrease/lowering is measured, and in what sample. It is unclear what is an amount “effective” to additively induce fetal hemoglobin – what does it mean to “additively induce”. Based on the teachings of the Specification, one cannot understand what is an “effective amount” of AN-233 and HU in claims 13, 16, and dependent claims.
One wishing to practice the instantly claimed invention would thus not recognize the metes and bounds for which Applicant seeks protection.
Appropriate clarification of the claim language is required.
In the interest of compact prosecution, claims 13, 16 are interpreted to be drawn to a pharmaceutical composition comprising AN-233 and hydroxyurea.
Claim Rejections- 35 USC 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Oseghale et al. (Blood Cells, Molecules and Diseases 2019, 79, 102345, p. 1-8, published online 9 July 2019, cited in IDS).
Oseghale teaches (Fig. 5, page 6) that AN-233, which is a prodrug of butyric acid and 5-ALA (page 2, left column, second paragraph), is effective to increase HbF expression in a -YAC transgenic mouse (in which -globin to -globin switching occurs during development, page 6, left column, first paragraph), which is an animal model of a -hemoglobinopathy, used as preclinical model (page 7, right column, second paragraph) for SCD and beta-thalassemia, a disease of instant claim 5. Oseghale teaches (page 6, left column) that mice were administered AN-233 200 mg/kg or 300 mg/kg dissolved in water by i.p. route; the levels of HbF increased 1.4-fold and 1.7-fold, respectively, at the two AN-233 doses administered.
Oseghale teaches (page 1, first paragraph under Introduction) that sickle cell disease (SCD) is a group of hematologic disorders that arise from mutations in the structural gene encoding a subunit of hemoglobin (Hb); a single point mutation A to T at the sixth codon of the beta-globin gene results in production of HbS; the homozygous form of the mutation produces sickle cell anemia, which is a disease of instant claims 3, 4, 6.
As such, a method of instant claims 1, 3-6 is anticipated by Oseghale.
Applicant may rely on the exception under 35 U.S.C. 102(b)(1)(A) to overcome this rejection under 35 U.S.C. 102(a)(1) by a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application, and is therefore not prior art under 35 U.S.C. 102(a)(1). Alternatively, applicant may rely on the exception under 35 U.S.C. 102(b)(1)(B) by providing evidence of a prior public disclosure via an affidavit or declaration under 37 CFR 1.130(b).
Claim Rejections- 35 USC 103
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) (“where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation”). See MPEP 2111.02. In this case, the body of claims 13-22 fully and intrinsically set forth all the limitations of the claimed invention, namely a composition comprising AN-233 (claim 13), or a composition comprising AN-233 and hydroxyurea (claims 14-22); the preambles only state the intended use of the composition. Thus, the preambles are not given any patentable weight.
"[T]he patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure." Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801,809 (Fed. Cir. 2002).
It is well settled that “intended use” of a composition or product, e.g., “for use as a medicament”, will not further limit claims drawn to a composition or product, so long as the prior art discloses the same composition comprising the same ingredients in an effective amount, as the instantly claimed. See, e.g., Ex parte Masham, 2 USPQ2d 1647 (1987) and In re Hack 114, USPQ 161
Claims 1, 5, 25-27 are rejected under 35 U.S.C. 103 as being unpatentable Oseghale et al. (Blood Cells, Molecules and Diseases 2019, 79, 102345, p. 1-8, published online 9 July 2019, cited in IDS).
Oseghale teaches (Fig. 5, page 6) that AN-233, which is a prodrug of butyric acid and 5-ALA (page 2, left column, second paragraph), is effective to increase HbF expression in a -YAC transgenic mouse (in which -globin to -globin switching occurs during development, page 6, left column, first paragraph), which is an animal model of a -hemoglobinopathy. Oseghale teaches (page 6, left column) that mice were administered AN-233 200 mg/kg or 300 mg/kg dissolved in water by i.p. route; the levels of HbF increased 1.4-fold and 1.7-fold, respectively, at the two AN-233 doses administered.
Oseghale does not teach that AN-233 is administered orally, locally or subcutaneously, as in instant claims 25-27.
It would have been obvious to administer AN-233 orally, locally or subcutaneously in the method of Oseghale, because oral, i.p., topical (local), or s.c. are well-known routes of administration of therapeutic agents, used interchangeably in a method of treatment.
As such, claims 1, 5, 25-27 are rejected as prima facie obvious.
Applicant may rely on the exception under 35 U.S.C. 102(b)(1)(A) to overcome this rejection under 35 U.S.C. 102(a)(1) by a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application, and is therefore not prior art under 35 U.S.C. 102(a)(1). Alternatively, applicant may rely on the exception under 35 U.S.C. 102(b)(1)(B) by providing evidence of a prior public disclosure via an affidavit or declaration under 37 CFR 1.130(b).
Claims 1, 3-10, 12-13, 16-17, 23-29 are rejected under 35 U.S.C. 103 as being unpatentable over Rephaeli et al. (US 2014/0024710, cited in IDS), in view of Atweh et al. (Hemoglobinopathies. ASH Education Program Book 2003 (1), pp. 14-39, cited in IDS).
Rephaeli teaches ([0157], [0159]) the compound below
PNG
media_image2.png
93
306
media_image2.png
Greyscale
PNG
media_image3.png
21
297
media_image3.png
Greyscale
,
which is the very compound AN-233 of the instant claims.
Rephaeli teaches [0169] that the co-drug above is hydrolyzed in vivo to one or more active compounds, such as 5-ALA and a carboxylic acid compound (which is butyric acid) that is active as an HDAC inhibitor. Thus, Rephaeli teaches that that 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate is a butyrate prodrug. Rephaeli teaches that 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate above provides synergistic results with respect to erythropoiesis and hemoglobin production compared to 5-ALA, butyric acid, or a mixture thereof [0169].
Rephaeli teaches that the compound induces a dramatic change in erythropoiesis and hemoglobin production [0169] and is effective in the treatment of anemia (claim 1).
Raphaeli teaches pharmaceutical compositions [0180] comprising compounds of the invention, to be administered (page 12, [0181]) for example, orally, as in instant claims 25, 28, or subcutaneously, as in instant claim 27, or topically/locally, as in instant claim 26; topical administration includes topical administration to the eye, as in instant claims 12, 29.
Rephaeli does not teach a method of treating a hemoglobinopathy, such as sickle cell disease, or beta-thalassemia, with 1-(butyryloxy)ethyl-5-amino-4-oxopentanoate (AN-233), as in instant claims 1, 3-9, 12, 25-27.
Rephaeli does not teach that the method further comprises administering hydroxyurea to the subject, as in instant claim 8, or wherein the subject is unresponsive to HU treatment, as in instant claim 9. Rephaeli does not teach a method of treating a hemoglobinopathy by orally administering a composition comprising AN-233 and hydroxyurea to the subject, as in instant claim 28.
Rephaeli does not teach a pharmaceutical composition comprising AN-233 and hydroxyurea, as in instant claims 13, 16, 24, wherein the composition is formulated for oral delivery, as in instant claim 23, or for local or subcutaneous delivery, as in instant claim 17.
Rephaeli does not teach treating hemoglobinopathy in patients suffering from retinopathy caused by SCD, as in instant claims 7, 29, by applying AN-233 topically to the eye, as in instant claims 12, 29.
Atweh et al. (Hemoglobinopathies. ASH Education Program Book 2003 (1), pp. 14-39) teach (page 20, left column, second paragraph) that butyrate is an HbF (fetal hemoglobin) -inducing agent in patients with sickle cell disease (SCD) and beta-thalassemia.
Atweh teaches that butyrate prodrugs namely arginine butyrate (page 20, left column, third paragraph) or sodium phenylbutyrate (page 20, left column, last paragraph) are effective to increase HbF levels in patients with SCD. Atweh teaches (page 20, right column, second paragraph) that butyrate’s effect on HbF production is at least in part mediated by inhibition of histone deacetylases (butyrate is HDAC inhibitor).
Atweh also teaches (page 20, left column, first paragraph) that hydroxyurea (HU), which is a therapeutic agent in instant claims 8-9, 13, 16, 17, 23, 24, 28, is the first HbF-inducing drug to be approved by the FDA for the treatment of SCD and is now widely used in the treatment of SCD patients throughout the world.
Atweh further teaches (page 20, right column, last paragraph, page 21, left column) combination therapy with hydroxyurea and butyrate. Atweh teaches that the use of butyrate and HU in combination therapy regimens induces HbF production in an additive or synergistic manner (page 21, left column, first paragraph). Atweh teaches (page 21, left column, first paragraph) that all patients who were enrolled in a combination therapy protocol consisting of HU for several months, followed by HU and butyrate, had a marked increase in their HbF levels after butyrate was added to HU.
Atweh also teaches (page 21, left column, second paragraph) that addition of butyrate to HU in SCD patients resulted in higher HbF levels, which are associated with less severe clinical outcomes.
Atweh also teaches (page 27, left column, third paragraph) that pathology consisting of drop-out of vessels in the retina, structures reminiscent of black sunbursts which are due to invasion of pigmented epithelial cells from the choroid, and loss of photoreceptors in regions where the underlying choroid has been destroyed, has been found in sickle mice retina; similar damage was found in human eyes from autopsies of sickle cell disease patients. Thus, Atweh teaches retinopathy caused by SCD in sickle cell patients, as in instant claims 7, 12, 29.
Atweh teaches that sickle cell disease (SCD) and thalassemia are monogenic disorders (page 25, right column, first paragraph) caused by mutations in the HBB gene (SCD page 26, left column, second paragraph; thalassemia page 30, left column, second paragraph).
It would have been obvious to combine the teachings of Rephaeli and Atweh to arrive at the instant invention. The person of ordinary skill in the art would have administered 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) to a subject suffering from a hemoglobinopathy such as sickle cell disease, or sickle cell anemia or beta-thalassemia, because Rephaeli teaches that 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) is a butyrate prodrug (AN-233 is hydrolyzed in vivo to butyric acid, which is active as an HDAC inhibitor), and Atweh teaches that butyrate, other butyrate prodrugs are effective to treat a hemoglobinopathy such as SCD or thalassemia. Thus, the person of ordinary skill in the art would have administered 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) to a subject suffering from a hemoglobinopathy with the expectation that, upon administration, AN-233 will be converted in vivo into butyrate, which is effective to treat said hemoglobinopathy.
Further, with respect to claim 25, 26, 27, the person of ordinary skill in the art would have administered AN-233 orally, or subcutaneously, or locally/topically because Rephaeli teaches that the compounds of the invention are to be administered, for example, orally or subcutaneously or topically/locally.
With respect to claims 8, 13, 16, 17, 23, 24, 28, the person of ordinary skill in the art would have been motivated to further administer hydroxyurea in the method of treatment (as in instant claim 8), or to combine AN-233 and HU in a pharmaceutical composition (as in instant claims 13, 16, 24), formulated for oral or local delivery (as in instant claims 17, 23), to be administered in the method (as in instant claim 28), because Rephaeli teaches that 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) is a butyrate prodrug which is hydrolyzed in vivo to butyric acid, and Atweh teaches the use of butyrate and HU in combination therapy regimens in patients with SCD. Thus, the person of ordinary skill in the art would have replaced butyrate with AN-233 in a combination/composition with HU, with the expectation that the resulting combination/composition will retain therapeutic effect in treating SCD.
Further, Rephaeli teaches that 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) is a butyrate prodrug which is hydrolyzed in vivo to butyric acid, Atweh teaches that butyrate prodrugs are effective to treat SCD, and Atweh teaches hydroxyurea (HU) as a therapeutic agent widely used in the treatment of SCD patients. Since AN-233 and HU are known/expected to treat SCD, it is considered prima facie obvious to combine them in a composition used for the same purpose. At least additive therapeutic effects would have been reasonably expected. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980).
Regarding the limitations “amount effective in the combination to lower OCTN1 expression; and/or additively induce fetal hemoglobin in the subject's red blood cells, when compared to treatment with hydroxyurea alone” in claims 16, 24, the examiner's position is that the properties of the composition, for example, ability to induce fetal hemoglobin in red blood cells, are inherent to the composition. Therefore, if the prior art teaches the composition or renders the composition obvious, then the properties are also taught or rendered obvious by the prior art. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990.) See MPEP 2112.01. The burden is shifted to Applicant to show that the prior art product does not possess or render obvious the same properties as the instantly claimed product.
With respect to claim 9, the person of ordinary skill in the art would have been motivated to further administer hydroxyurea in the method of treatment, when the patient is unresponsive to treatment with hydroxyurea alone, because Atweh teaches that patients who were enrolled in a combination therapy protocol consisting of HU for several months, followed by HU and butyrate, had a marked increase in their HbF levels after butyrate was added to HU, and Atweh also teaches that addition of butyrate to HU in SCD patients resulted in higher HbF levels, which are associated with less severe clinical outcomes. Thus, the person of ordinary skill in the art would have administered AN-233 in combination with HU to SCD patients who were not responsive to HU alone, with the expectation that the combination of HU and butyrate (generated in vivo from butyrate prodrug AN-233) will increase HbF more than administration of HU alone, and the resulting increased levels of HbF will result in improved therapeutic effect in said SCD patients.
With respect to claims 7, 12, 29, the person of ordinary skill in the art would have administered AN-233 to a patient suffering from SCD and retinopathy, because Atweh teaches that retinopathy is a well-known complication of SCD. Thus, the person of ordinary skill in the art would have administered AN-233 to a patient suffering from SCD and retinopathy, with the expectation that AN-233 will be effective to treat SCD in such a patient subpopulation. Further, administering AN-233 topically to the eye is obvious, because choosing a topical route of administration of a therapeutic agent in a method of treatment is within the skill of the artisan.
As such, claims 1, 3-9, 12-13, 16-17, 23-29 are rejected as prima facie obvious.
Claims 1, 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Rephaeli et al. (US 2014/0024710, cited in IDS), in view of Atweh et al. (Hemoglobinopathies. ASH Education Program Book 2003 (1), pp. 14-39, cited in IDS), in further view of Yahouedehou et al. (The Pharmacogenomics Journal 2018, 18, 730-739, published online 12 September 2018, cited in IDS).
Rephaeli teaches ([0157], [0159]) the compound below
PNG
media_image2.png
93
306
media_image2.png
Greyscale
PNG
media_image3.png
21
297
media_image3.png
Greyscale
,
which is the very compound AN-233 of the instant claims.
Rephaeli teaches [0169] that the co-drug above is hydrolyzed in vivo to one or more active compounds, such as 5-ALA and a carboxylic acid compound (which is butyric acid) that is active as an HDAC inhibitor. Thus, Rephaeli teaches that that 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate is a butyrate prodrug. Rephaeli teaches that 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate above provides synergistic results with respect to erythropoiesis and hemoglobin production compared to 5-ALA, butyric acid, or a mixture thereof [0169].
Rephaeli teaches that the compound induces a dramatic change in erythropoiesis and hemoglobin production [0169] and is effective in the treatment of anemia (claim 1).
Rephaeli does not teach a method of treating a hemoglobinopathy, such as sickle cell disease, or beta-thalassemia, with 1-(butyryloxy)ethyl-5-amino-4-oxopentanoate (AN-233),
further comprises administering hydroxyurea to the subject, as in instant claim 8, wherein the subject is unresponsive to HU treatment, as in instant claim 9, wherein the subject expresses lower levels of OCTN1 than patients who respond to hydroxyurea, as in instant claim 10.
Atweh et al. (Hemoglobinopathies. ASH Education Program Book 2003 (1), pp. 14-39) teach (page 20, left column, second paragraph) that butyrate is an HbF (fetal hemoglobin) -inducing agent in patients with sickle cell disease (SCD) and beta-thalassemia.
Atweh teaches that butyrate prodrugs namely arginine butyrate (page 20, left column, third paragraph) or sodium phenylbutyrate (page 20, left column, last paragraph) are effective to increase HbF levels in patients with SCD. Atweb teaches (page 20, right column, second paragraph) that butyrate’s effect on HbF production is at least in part mediated by inhibition of histone deacetylases (butyrate is HDAC inhibitor).
Atweh also teaches (page 20, left column, first paragraph) that hydroxyurea (HU), which is a therapeutic agent in instant claims 8-10, is the first HbF-inducing drug to be approved by the FDA for the treatment of SCD and is now widely used in the treatment of SCD patients throughout the world.
Atweh further teaches (page 20, right column, last paragraph, page 21, left column) combination therapy with hydroxyurea and butyrate, which is relevant to instant claims 8-10. Atweh teaches that the use of butyrate and HU in combination therapy regimens induces HbF production in an additive or synergistic manner (page 21, left column, first paragraph). Atweh teaches (page 21, left column, first paragraph) that all patients who were enrolled in a combination therapy protocol consisting of HU for several months, followed by HU and butyrate, had a marked increase in their HbF levels after butyrate was added to HU.
Atweh also teaches (page 21, left column, second paragraph) that addition of butyrate to HU in SCD patients resulted in higher HbF levels, which are associated with less severe clinical outcomes.
Yahouedehou (The Pharmacogenomics Journal 2018, 18, 730-739) teaches (page 737, left column, first paragraph) OCTN1 as a pharmacogenomic biomarker that can predict hydroxyurea (HU) treatment efficacy in sickle cell disease patients.
Yahouedehou teaches (page 733, right column, second paragraph) that OCTN1 expression mediated by HU suggests the pivotal role of OCTN1 in the efficacy of HU.
It would have been obvious to combine the teachings of Rephaeli, Atweh and Yahouedehou to arrive at the instant invention. The person of ordinary skill in the art would have administered 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) in combination with hydroxyurea to a subject suffering from sickle cell disease, where the patient is unresponsive to treatment with hydroxyurea alone, and the patient expresses lower levels of OCTN1 than patients who respond to hydroxyurea, because
Rephaeli teaches that 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) is a butyrate prodrug (AN-233 is hydrolyzed in vivo to butyric acid), and
Atweh teaches that butyrate, other butyrate prodrugs are effective to treat SCD, and
Atweh teaches that SCD patients who were enrolled in a combination therapy protocol consisting of HU for several months, followed by HU and butyrate, had a marked increase in their HbF levels after butyrate was added to HU, and Atweh also teaches that addition of butyrate to HU in SCD patients resulted in higher HbF levels, which are associated with less severe clinical outcomes, and
Yahouedehou teaches that higher OCTN1 expression levels in patients correlate with better response/efficacy of hydroxyurea in treating SCD.
Thus, the person of ordinary skill in the art would have administered AN-233 in combination with HU to SCD patients who were not responsive to HU alone, and who express lower OCTN1 levels (said lower levels of OCTN1 in patients correlate with lower response to/efficacy of hydroxyurea in treating SCD (Yahouedehou)), with the expectation that the combination of HU and butyrate (generated in vivo from butyrate prodrug AN-233) will increase HbF more than administration of HU alone, and the resulting increased levels of HbF will result in improved therapeutic effect in said SCD patients.
As such, claims 1, 8-10 are rejected as prima facie obvious.
Double patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-10, 12-13, 16-17, 23-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-17 of U.S. Patent No. 9,018,257 (cited in IDS), in view of Atweh et al. (Hemoglobinopathies. ASH Education Program Book 2003 (1), pp. 14-39, cited in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 8-17 of U.S. Patent No. 9,018,257 render obvious the instant claims.
Claims 8-17 of U.S. Patent No. 9,018,257 are drawn to a compound of formula (I) or a pharmaceutical composition thereof; the genus of compounds of formula (I) encompasses the instant compound AN-233. Further, compound (C) in claim 14 of U.S. Patent No. 9,018,257 is a direct structural homolog ethyl vs. methyl of AN-233. Claim 17 of U.S. Patent No. 9,018,257 is drawn to pharmaceutical compositions in a form suitable for oral administration, or topical administration.
The Specification of U.S. Patent No. 9,018,257 teaches that the co-drugs of formula (I) are hydrolyzed in vivo to one or more active compounds, such as 5-ALA and a carboxylic acid compound (butyric acid) that is active as an HDAC inhibitor.
Atweh is as above.
It would have been obvious to combine the teachings of claims 8-17 of U.S. Patent No. 9,018,257 and Atweh to arrive at the instant invention. The person of ordinary skill in the art would have administered 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) to a subject suffering from a hemoglobinopathy such as sickle cell disease, or sickle cell anemia or beta-thalassemia, because claims 8-17 of U.S. Patent No. 9,018,257 teaches that a compound of formula (I) such as 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) is a butyrate prodrug (AN-233 is hydrolyzed in vivo to butyric acid, which is active as an HDAC inhibitor), and Atweh teaches that butyrate, other butyrate prodrugs are effective to treat a hemoglobinopathy such as SCD or thalassemia. Thus, the person of ordinary skill in the art would have administered 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) to a subject suffering from a hemoglobinopathy with the expectation that, upon administration, AN-233 will be converted in vivo into butyrate, which is effective to treat said hemoglobinopathy. Further, with respect to claims 25-27, the person of ordinary skill in the art would have administered AN-233 orally, or topically, because claim 17 of U.S. Patent No. 9,018,257 teaches that the compounds of the invention are to be administered, for example, orally, or topically.
With respect to claims 8, 13, 16, 17, 23, 24, 28, the person of ordinary skill in the art would have been motivated to further administer hydroxyurea in the method of treatment (as in instant claim 8), or to combine AN-233 and HU in a pharmaceutical composition (as in instant claims 13, 16, 24), formulated for oral or local delivery (as in instant claims 17, 23), to be administered in the method (as in instant claim 28), because claims 8-17 of U.S. Patent No. 9,018,257 teach that a compound of formula (I) such as 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) is a butyrate prodrug which is hydrolyzed in vivo to butyric acid, and Atweh teaches the use of butyrate and HU in combination therapy regimens in patients with SCD. Thus, the person of ordinary skill in the art would have replaced butyrate with AN-233 in a combination/composition with HU, with the expectation that the resulting combination/composition will retain therapeutic effect in treating SCD.
Further, claims 8-17 of U.S. Patent No. 9,018,257 teach that a compound of formula (I) such as 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) is a butyrate prodrug (AN-233 Rephaeli teaches that 1-(butyryloxy)ethyl 5-amino-4-oxopentanoate (AN-233) is a butyrate prodrug which is hydrolyzed in vivo to butyric acid, Atweh teaches that butyrate prodrugs are effective to treat SCD, and Atweh teaches hydroxyurea (HU) as a therapeutic agent widely used in the treatment of SCD patients. Since AN-233 and HU are known/expected to treat SCD, it is considered prima facie obvious to combine them in a composition used for the same purpose. At least additive therapeutic effects would have been reasonably expected. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980).
With respect to claim 9, the person of ordinary skill in the art would have been motivated to further administer hydroxyurea in the method of treatment, when the patient is unresponsive to treatment with hydroxyurea alone, because Atweh teaches that patients who were enrolled in a combination therapy protocol consisting of HU for several months, followed by HU and butyrate, had a marked increase in their HbF levels after butyrate was added to HU, and Atweh also teaches that addition of butyrate to HU in SCD patients resulted in higher HbF levels, which are associated with less severe clinical outcomes. Thus, the person of ordinary skill in the art would have administered AN-233 in combination with HU to SCD patients who were not responsive to HU alone, with the expectation that the combination of HU and butyrate (generated in vivo from butyrate prodrug AN-233) will increase HbF more than administration of HU alone, and the resulting increased levels of HbF will result in improved therapeutic effect in said SCD patients.
With respect to claims 7, 12, 29, the person of ordinary skill in the art would have administered AN-233 to a patient suffering from SCD and retinopathy, because Atweh teaches that retinopathy is a well-known complication of SCD. Thus, the person of ordinary skill in the art would have administered AN-233 to a patient suffering from SCD and retinopathy, with the expectation that AN-233 will be effective to treat SCD in such a patient subpopulation. Further, administering AN-233 topically to the eye is obvious, because choosing a topical route of administration of a therapeutic agent in a method of treatment is within the skill of the artisan.
As such, instant claims 1, 3-10, 12-13, 16-17, 23-29 are rejected.
Conclusion
Claims 1, 3-10, 12-13, 16-17, 23-29 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY S. LUNDGREN can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/IRINA NEAGU/Primary Examiner, Art Unit 1629