DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/26/2026 and 07/24/2024 have been considered by the examiner.
Status of the Claims
The claims filed 07/24/2024 are under consideration.
Claims 1-13 are pending.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Rejections not reiterated herein have been withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
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.
Claim 12 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating Fabry’s disease, does not reasonably provide enablement for 1) preventing Fabry’s disease.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice a method commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized in Ex parte Forman, 230 USPQ 546 (BPAI 1986) and reiterated by the Court of Appeals in In re Wands, 8 USPQ2nd 1400 at 1404 (CAFC 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
Nature of the Invention: Claim 12 recites wherein the liquid formulation is used to prevent or treat Fabry disease.
Breadth of the claims: The scope of claims 12 extends to the prevention of Fabry disease.
The quantity of experimentation necessary/state of the prior art/relative skill of those in the art/ predictability or unpredictability of the art:
Lysosomal storage diseases are genetically inherited diseases. The only known methods for prevention are preimplantation genetic diagnosis or prenatal diagnosis and termination of pregnancy. See Altarescu, Molecular Biology International, 2012, Abstract and Introduction.
Lysosomal storage diseases (LSD) are multi-systemic disorders and affect multiple organ systems. Not all lysosomal storage diseases have an established molecular study for diagnostic screening, however, where molecular diagnosis has been established, prenatal diagnosis appears to be the only means for determining if a subject is in need of preventing a lysosomal storage disease. See Fabry Disease, Cleveland Clinic, 2023, e.g., Prevention, spanning pp. 3-4 and Altarescu, Molecular Biology International, 2012: pg. 9, Prevention of LSDs in India.
Sheth, The Lancet Regional Health, Southeast Asia, 9, 2023 teaches LSDs are heterogenous in clinical presentation and genetic presentation. The effect of gene variant on the protein activity and resulting disease course is not well understood in the case of all lysosomal storage disorders. There is phenotype variability seen in LSD patients harboring the same gene variant; additional factors include epigenetic factors, effect of modifier genes, and environmental factors (Sheth, e.g., ¶ spanning pp. 1-2).
Since LSDs, including Fabry disease, are multi-systemic disorders with a heterogenous genetic relationship to disease presentation, there is no clear technique for identifying subjects in need of preventing lysosomal storage diseases generally apart from genetic testing. Even if such an identification can be made before presentation of symptoms, it cannot be predicted that Fabry disease could be prevented by administering the recited fusion protein based on the state of the prior art alone or in combination with the present disclosure. There is still a need for preparing an algorithm for early clinical suspicion of LSDs (Sheth, e.g., pg. 4, c2).
The art, as of the filing date of the presently claimed invention, considered Fabry disease as not preventable since it was not clear which lysosomal storage disease could be effectively prevented prior to disease onset even if known genetic factors are identified. Prevention of any lysosomal storage disease would require a therapy which prevents the disease by eliminating or modifying an unknown combination of genetic phenotypes, epigenetic factors, modifier genes, and environmental factors. As of 2012 and 2023, the correlation between genetic markers and specific lysosomal storage disorder disease progression was not known. The risk is so high, and prognosis so poor, that even as of 2023, effective prevention can only be made by avoiding implantation of embryo’s identified with known genetic factors (Altarescu, e.g., Abstract and Fabry Disease, prevention spanning pp. 3-4).
To the extent that claim 12 encompasses eliminating the risk of Fabry’s disease altogether, the present specification does not appear to provide any evidence that Fabry’s disease could be prevented by administering the recited fusion protein using known administration routs. The specification indicates the fusion protein is effective for enzyme replacement therapy (Specification, e.g., ¶ 196). However, the specification does not teach a protocol for administration of the recited fusion protein which changes the underlying genetic disease deficiency and eliminates the risk of recurrence.
The currently claimed invention is not commensurate in scope with the limited guidance provided in the specification. Since criteria for identifying candidates for successful prevention were unestablished, and since there is no guidance in the specification filling this gap, one skilled in the art would have to embark on a trial-and-error course of experimentation to prevent Fabry’s disease. Based on the understanding those skilled in the art and the state of the art at the time the invention was filed, one skilled in the art would be required to perform undue experimentation to discover how to use the presently claimed invention to prevent lysosomal storage diseases.
Therefore, as of the filing date of the presently claimed invention, the present specification is not enabling for using the full scope of the claimed invention as it pertains to preventing lysosomal storage diseases by administering an alpha-galactosidase-Fc fusion protein to a subject in need thereof.
Conclusion - although the level of skill for an ordinary person in the art is high, the Examiner finds that the other Wands factors suggest a conclusion that the skilled artisan would not be able to use the instant invention over the full scope of claim 12 without undue experimentation.
Claims 12 and 13 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 pre-AIA the applicant regards as the invention.
Both of the rejected claims depend from claim 1 and refer to a use of the formulation of claim 1. It is not clear if claims 12 and 13 were intended to be product or process claims. However, because of their dependency from claim 1, the claims have been interpreted as intended uses.
Claim 13 recites the liquid formulation is administered via a subcutaneous route. A product and process in the same claim is indefinite. See MPEP 2173.05(p). Therefore claim 13 has been interpreted to further limit the subject matter of claim 1 as a formulation which may be administered subcutaneously.
Clarification is required.
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 of this title, 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.
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.
Claims 1-10 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Jung, US 20210009984 and Andersen, WO 2020206320 (cited on Applicant’s IDS dated 03/26/2026).
Andersen teaches pharmaceutical compositions comprising an enzyme replacement therapy Fc fusion polypeptide for treating lysosomal storage disorders, a buffer, an isotonicity agent, a surfactant, and a stabilizer, wherein the pH is about 5.5 to 7.0 (Andersen, e.g., Abstract and pp. 57-58, pg. 81). The claimed pH range is within the range suggested by Andersen. Applicable to claims 2 and 5: Andersen teaches the formulation wherein the buffer is phosphate or histidine or citrate, or acetate (Andersen, entire document, e.g., pg. 37:16-25 and claim 2). Applicable to claims 3 and 4: Andersen teaches the isotonic agent as sodium chloride in the claimed range for improved stability (Andersen, entire document, e.g., pp. 40-41, e.g., pg. 41:20-25). Applicable to claims 6-7: Andersen teaches the formulation further comprising a surfactant, e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 in an amount ranging from 0.01 – 5 mg/ml, e.g., 0.5-0.7 mg/ml (Andersen, e.g., pp. 43-44). Since 0.7 mg/ml is 0.07 % w/v = g/100ml (0.7 x 100%/1000mg), Andersen teaches a single value in the claimed range, and the claimed range is within the range suggested by Andersen. Andersen teaches the formulation maintains therapeutic efficacy of the protein therapeutic over extended periods of time (Anderssen, e.g., ¶ spanning pp. 89-90). Andersen exemplifies a number of formulations containing protein in an amount within the claimed range, buffers, e.g., phosphate, histidine, or acetate, a pH ranging from 5.5 to 6.5, and sodium chloride in an amount within the claimed range. See Andersen, e.g., example 3 starting at pg. 100. Andersen further exemplifies a number of formulations further comprising a surfactant, e.g., polysorbate 80. See Andersen, e.g., example 4 starting at pg. 107.
Andersen does not expressly teach an alpha-galactosidase-Fc fusion protein.
Jung teaches liquid formulations, e.g., solutions or suspensions (Jung, e.g., 0163), and injectable (Jung, e.g., example 5), which contain an alpha-galactosidase-Fc fusion protein (Jung, e.g., example 5 and seq id no: 13). The fusion protein having and seq id no: 13 meets the amino acid sequence limitations of claims 8-10 because Jung’s alpha-galactosidase-Fc fusion protein has the same sequence required by Seq ID No: 4. The claimed Seq ID No: 1 is the sequence of native alpha-galactosidase which is present in Jung’s alpha-galactosidase-Fc fusion protein. The dimer structure is found in Jung, e.g., Example 2-2, 0209-0210. Jung teaches the formulation comprising a buffering agent, an isotonic agent and stabilizing agent (Jung, e.g., 0162). Jung teaches the formulation useful for treating or preventing Fabry’s disease (claim 45, 0003-0004, 0096, 0155: Fabry’s disease which occurs due to the lack of, or deficiency in activity of, alpha galactosidase A) when administered subcutaneously (Jung, e.g., example 5).
However, Jung does not expressly teach the liquid formulation comprising the fusion protein at a concentration of 10 mg/mL to 90 mg/ml; a buffer for maintaining a pH of the liquid formulation in a range of 5.5 to 6.5; and an amino acid at a concentration of 0.5% (w/v) to 4.0% (w/v).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the presently claimed invention to combine the teachings of Jung and Andersen to arrive at the presently claimed subject matter with a reasonable expectation of success.
Starting from Jung, the skilled artisan would have been motivated to adopt known formulation techniques known from Andersen for better therapeutic efficacy by improving stability of Jung’s fusion protein within the formulation in the same way with a reasonable expectation of success. The skilled artisan would have had a reasonable expectation of success because Andersen teaches formulations which improve stability of fusion proteins useful for enzyme replacement therapy in lysosomal storage disorders and because Jung teaches an alpha-galactosidase-Fc fusion protein useful for enzyme replacement therapy in lysosomal storage disorders such as Fabry’s disease.
Starting from Andersen, the skilled artisan would have been motivated to modify Andersen’s stabilized fusion protein formulations using other known enzyme replacement therapy fusion proteins, such as Jung’s alpha-galactosidase-Fc fusion protein, to predictably arrive at alternative fusion protein stabilized formulations useful for treating the same lysosomal disorder, e.g., Hunter syndrome, with a reasonable expectation of success. The skilled artisan may have seen this as combining two known fusion proteins known and used for treating Hunter syndrome into a single formulation useful for the same purpose. Alternatively, the skilled artisan may have seen this modification as the substitution of one known fusion protein useful for treating lysosomal storage disorders for another to arrive at an alternative formulation useful for treating lysosomal storage disorders. Since Jung teaches the alpha-galactosidase-Fc fusion protein may be used to treat lysosomal storage disorders, and would benefit from formulations which improve protein stability, the skilled artisan would have had a reasonable expectation of success.
Accordingly, the subject matter of claims 1-10 and 12-13 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Jung, US 20210009984 and Andersen, WO 2020206320 (cited on Applicant’s IDS dated 03/26/2026) as applied to claims 1-10 and 12-13 above, and further in view of Chang, US 20140127227.
The combined teachings of Jung and Andersen teach a formulation according to claim 1, but do not expressly teach the formulation comprising serine.
Chang teaches protein formulations containing amino acids (Chang, e.g., Title, Abstract, claims), wherein serine may be present in an amount of about 1.05 % (w/v). Serine is effective to prevent aggregation and improve viscosity for injection. See Chang, e.g., 0022 and 0041 and 0194, Table 4. Chang teaches serine is effective wherein the protein is α-galactosidase A (Chang, e.g., 0035). Chang more generally teaches serine is effective at a concentration of at least 0.01 % w/v (Chang, e.g., claim 18).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the presently claimed invention to modify formulations containing alpha-galactosidase-Fc fusion protein, and histidine in amounts suggested by Jung and Andersen by including serine in an amount of at least 0.01 % w/v such as 1.05 % w/v as suggested by Chang with a reasonable expectation of success. The skilled artisan would have been motivated to look to Chang since Chang suggests serine will improve stability and viscosity of injectable formulations of α-galactosidase A which is the enzyme replaced by Jung’s fusion protein and contains the α-galactosidase A sequence for its biological effect. The skilled artisan would have had a reasonable expectation of success because the combined teachings of Jung and Anderson teach stabilized formulations containing α-galactosidase A fusion proteins and histidine.
Accordingly, the subject matter of claim 11 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the presently claimed invention, absent evidence to the contrary.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claim(s) 1-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-2, 3-13, and 15-22 of US 18832304.
Although the claims at issue are not identical, they are not patentably distinct from each other because: The reference claims teach a liquid formulation comprising aqueous solution comprising: the fusion protein at a concentration of 5 mg/mL to 50 mg/mL; 10 mM to 30 mM histidine; 0.002% (w/v) to 0.1% (w/v) polysorbate 20; 50 mM to 200 mM sodium chloride; and 1.0% (w/v) to 4.0% (w/v) serine (claim 16). The fusion protein is α-galactosidase A is linked to an immunoglobulin Fc region (claim 1). The formulation is useful for treating or preventing Fabry disease (claim 18). Since the formulation is a liquid, it appears to be suitable as a subcutaneous formulation. The lyophilized formulation is made from a liquid formulation within the scope of the present claims. In this respect the presently claimed invention is anticipated by the invention of the reference claims. Alternatively, since the reference claims teach the lyophilized formulation reconstituted with water, the presently claimed invention would have been obvious to one of ordinary skill in the art. For example, the concentration of the fusion protein in the reconstituted formulation has a concentration of fusion protein overlapping with that of the aqueous formulation used to make the lyophilized formulation. That is, the skilled artisan would have found it obvious to reconstitute the lyophilized solution to have concentrations similar to those reported in claim 16 for use in treating Fabry disease.
Accordingly, the subject matter of claims 1-13 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM A CRAIGO whose telephone number is (571)270-1347. The examiner can normally be reached on Monday - Friday, 9am - 6pm, PDT.
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/WILLIAM CRAIGO/Examiner, Art Unit 1615
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