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 09/28/2026 has been considered by the examiner.
Status of the Claims
The claims and remarks filed 09/28/2026 have been considered.
Claims 1-13 are pending.
Newly amended claims 12-13 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
Inventions of the liquid formulation of Group I, claims 1-11, and the method of treatment of Group II, claims 12-13, are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case the product as claimed may be used in a materially different process, i.e., formulating a lyophilized powder. See Andersen, WO 2020206320, e.g., pp. 48-49.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 12-13 have been withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 1-11 remain rejected. Claims 12-13 are withdrawn.
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.
Withdrawn
The rejection of claim 12 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 has been withdrawn because of Applicant’s amendment.
The rejection of claims 12 and 13 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 has been withdrawn because of Applicant’s amendment.
The rejection of claims 1-10 and 12-13 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) has been withdrawn because of Applicant’s amendment. The amendment incorporates the serine limitation of previous claim 11 into claim 1 as well as specifying a histidine buffer.
Response to Arguments
With respect to the rejection of claims 1-11 under 35 U.S.C. 103 based on Jung, US 20210009984 and Andersen, WO 2020206320 (cited on Applicant’s IDS dated 03/26/2026) and further in view of Chang, US 20140127227.
Applicant’s arguments, see remarks, filed 09/28/2026, with respect to claims 1-11 as amended have been fully considered but are not persuasive.
Applicant has argued that Chang fails to overcome the deficiencies of Jung and Andersen. Applicant has argued that Chang merely teaches that serine may be included in formulations containing non-fused a-galactosidase A. Applicant argues the formulations described in Chang differ substantially from those instantly claimed. Applicant argues Chang utilizes non-fused a-galactosidase A at substantially lower protein concentrations and employs phosphate- and mannitol-based formulations rather than formulations buffered with histidine or a salt thereof. Applicant has argued that Chang fails to provide a basis for reasonably expecting that serine would provide the same stabilizing effect in the claimed high-concentration liquid formulation comprising an a-galactosidase A-Fc fusion protein.
These arguments are unpersuasive. Andersen teaches a protein concentration overlapping with, and within, the claimed range, e.g., 5-50 mg/mL (Andersen, e.g., claim 26), e.g., 10 mg/mL in a 20 mM histidine buffer with 50 mM sodium chloride (Andersen, e.g., Example 3, table 3.1, pg. 100). This suggests similar properties were expected over Andersen’s range. There is no evidence Chang’s protein concentration is critical for improved stability. Andersen suggests histidine buffers and phosphate buffers as alternatives (Andersene, e.g., claim 2). From Andersen, the skilled artisan would likely have concluded that Chang’s improved stability result with serine and phosphate buffer could be extrapolated to known buffer alternatives including histidine buffers. Since the therapeutic efficacy of the fusion proteins in Jung and Andersen are based on the enzyme segment of the fusion protein, the skilled artisan would have reasonably expected that Chang’s teaching suggesting serine for improving the stability of α-Gal would also improve Jung’s α-Gal-Fc fusion protein - which relies on α-Gal activity - when formulated in a histidine or phosphate buffer as suggested by Andersen.
Applicant has argued that the results demonstrated in Examples 4-2 and 4-3 of the specification as filed, including the proportional increase in Tm with increasing serine concentration, significant inhibition of aggregation at a serine concentration of 1.0%, and the stabilizing effect of serine superior to that of arginine, would not have been reasonably expected based on the cited references.
This argument is unpersuasive.
It is not clear that a statistical analysis was performed on the data presented. It is not clear that the proffered data is statistically significant. The evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” See MPEP 716.02(b).
Further, since it was known from Chang that serine was useful to improve stability of α-Gal, it does not appear to be unexpected that serine improves stability of α-Gal-Fc which contains the same enzyme. “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” See MPEP 716.02(c), II.
Further still, the claimed invention is not commensurate in scope with the proffered data. See MPEP 716.02(d). The argued result was obtained using a composition containing a single concentration of fusion protein, a single histidine buffer concentration (20 mM), a single sodium chloride concentration (50 mM), a single concentration of polysorbate 20 (0.05%), three concentrations of serine (1.0%, 2.0%, and 4.0%), and a single pH of 5.5. See spec, e.g., pp. 35-36, Table 5.
In contrast, the claimed invention encompasses compositions comprising the fusion protein at a concentration of 10 mg/mL to 90 mg/mL (broader range); histidine or a salt thereof (in any concentration) as a buffer for maintaining a pH of the liquid formulation in a range of 5.5 to 6.5 (broader pH range); and serine at a concentration of 1.0% (w/v) to 4.0% (w/v). The claim is silent to polysorbate 20 and concentration thereof. The claim is silent to sodium chloride and concentration thereof. The nature and concentration of the isotonicity agent affects stability (Spec, e.g., Experimental Example 3-2, ¶ 314-322). There is an insufficient variety of compositions within the claimed scope to allow the skilled artisan to extrapolate the proffered data over the full scope of the claimed invention.
With respect to the double patenting rejection:
Applicant's arguments filed 09/28/2026 have been fully considered but they are not persuasive.
Applicant takes the position that the instantly claimed formulation is patentably distinct from the formulation claimed in the '304 application. Applicant argues that the instant claims specify a liquid formulation comprising a fusion protein in which a-galactosidase A is fused to an immunoglobulin Fc region, histidine or a salt thereof as a buffer for maintaining a pH of the liquid formulation in a range of 5.5 to 6.5, and serine at a concentration of 1.0% (w/v) to 4.0% (w/v). Thus, amended claim 1 is directed to a liquid formulation comprising an a-galactosidase A-Fc fusion protein at a high concentration of 10 mg/mL to 90 mg/mL.In contrast, Applicant argues that the '304 application claims a lyophilized formulation comprising a fusion protein in which a-galactosidase A is linked to an immunoglobulin Fc region, the lyophilized formulation comprising a mixture prepared by lyophilizing an aqueous solution comprising the fusion protein at a concentration of 5 mg/mL to 50 mg/mL, a buffer with a pH of 5.5 to 7.0, and an amino acid at a concentration of 0.5% (w/v) to 4.0% (w/v). Applicant argues that the instantly claimed formulation and the lyophilized formulation claimed in the'304 application are distinct formulations in terms of physical form and stabilization mechanism. Applicant argues that the '304 claims require an aqueous solution to undergo lyophilization to produce the claimed lyophilized product, whereas the instant claims are directed to maintaining the a- galactosidase A-Fc fusion protein in liquid form.
These arguments are unpersuasive.
As noted by Applicant, the reference claims teach an aqueous solution comprising the fusion protein at a concentration of 5 mg/mL to 50 mg/mL, a buffer with a pH of 5.5 to 7.0, and an amino acid at a concentration of 0.5% (w/v) to 4.0% (w/v). Further, 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). Thus, the skilled artisan would have arrived at the liquid formulation set forth in the reference claims, which is within the scope of the presently claimed invention. 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.
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 1-11 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) and further in view of Chang, US 20140127227.
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 formulations containing fc fusion protein in an amount within the claimed range, e.g., 10 mg/mL, buffers, e.g., 20 mM histidine, a pH ranging from 5.5 to 6.5, and sodium chloride in an amount within the claimed range (50 mM). See Andersen, e.g., example 3 starting at pg. 100. Andersen further exemplifies formulations further comprising a surfactant, e.g., polysorbate 80. See Andersen, e.g., example 4 starting at pg. 107. Phosphate and histidine are each known as buffers (Andersen, e.g., pg. 37 and example 3, e.g., pg. 100).
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.
Andersen teaches the formulations may further comprise an amino acid as a stabilizer (Andersen, e.g., pp. 44-47). The combined teachings of Jung and Andersen do not teach the formulation further 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) (Chang, e.g., 0041). 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 and 0221). 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.
Applicable to claim 2: 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 two known buffers, e.g., histidine and phosphate, with a reasonable expectation of success. This modification is the combination of two known buffers each taught by the art to be useful for the same purpose to form a third composition to be used for the same purpose. See MPEP 2144.06, I. The skilled artisan would have had a reasonable expectation of success since the skilled artisan would have expected similar pH stabilizing properties from the buffers.
Applicable to claim 5: Chang teaches at least alanine and glycine as additional amino acids which stabilize α-galactosidase at a concentration of 1% (Chang, e.g., 0035, 0211:Table 7, and 0220-0221).
Accordingly, the subject matter of claims 1-11 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) 1-11 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 like those reported in claim 16 for use in treating Fabry disease.
Accordingly, the subject matter of claims 1-11 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.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Correspondence
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.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A WAX can be reached on 571-272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM CRAIGO/Examiner, Art Unit 1615
/SUSAN T TRAN/Primary Examiner, Art Unit 1615
