DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Election/Restrictions
Applicant’s election without traverse of the following species:
Pompe disease as the elected subject species; and
Human acid alpha-glucosidase as the elected therapeutic species
are maintained.
Claims 12-19 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on April 16, 2026, wherein claim 1 is amended; claims 2-11, 20-22 and 26-54 are cancelled; claims 12-19 and 23-25 are unchanged; and claims 55-58 are newly added. Specifically, applicant amends claim 1 by adding new limitation that recites “wherein the subject is administered the therapeutic for more than one cycle of a dosing regimen, wherein the effective amount of methotrexate is administered in a single cycle of the dosing regimen of the therapeutic, wherein methotrexate is not administered in subsequent cycles of the dosing regimen, wherein the subject is a human with Pompe disease and the therapeutic is human acid alpha-glucosidase, wherein immune tolerance toward the therapeutic is assessed by measuring anti-human acid alpha-glucosidase antibody in the subject”.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 12-19, 23-25 and 55-58 are pending. Claims 12-19 remain withdrawn.
Claims 1, 23-25 and 55-58 are under examination in accordance with the elected species.
Priority
The instant application 18/141,128 filed on April 28, 2023 is a continuation of U.S. Patent Application No. 16/828,407 filed on March 24, 2020, which is a continuation of U.S. Patent Application No. 14/116,486 that is a 371 of PCT/US2012/036405 filed on May 3, 2012, which claims priority to, and the benefits of U.S. Provisional Application No. 61/486,697 filed on May 16, 2011.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 16, 2026 was filed after the mailing date of the Non-Final Office Action on December 16, 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Action Summary
Acknowledgement is made of the receipt and entry of the amendment to the specification filed on April 16, 2026.
Applicant’s amendment to the specification overcome each and every objection previously sets forth in the Non-Final Office Action mailed on December 16, 2025.
Claims 1, 7, 11, 20, 22-25 and 54 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph are withdrawn in light of the claim amendment that added the limitation of “wherein the subject is a human with Pompe disease and the therapeutic is human acid alpha-glucosidase".
Claims 1, 7, 20, 22-25 and 54 rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Joseph et al. (Clin Exp Immunol, 2008. Vol. 152(1): 138-146; cited in the IDS filed on 8/10/2023) are withdrawn in light of the claim amendment that incorporates the new limitation.
Claims 1, 7, 11, 20, 22-25 and 54 rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Joseph et al. (Clin Exp Immunol, 2008. Vol. 152(1): 138-146; cited in the IDS filed on 8/10/2023) are withdrawn in light of the claim amendment that incorporates the new limitation; However, upon further consideration, the rejection has been reapplied as necessitated by amendment for the reasons set forth herein.
Claims 1, 7, 11, 20, 22-25 and 54 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,672,802 В2 (referred to herein as reference patent), in view of Joseph et al. (Clin Exp Immunol, 2008. Vol. 152(1): 138-146; cited in the IDS filed on 8/10/2023) are withdrawn in light of the claim amendment that incorporates the new limitation; However, upon further consideration, the rejection has been reapplied as necessitated by amendment for the reasons set forth herein.
Claims 1, 7, 11, 20, 22-25 and 54 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 12-15 of U.S. Patent No. 12,213,979 B2 (referred to herein as reference patent), in view of Joseph et al. (Clin Exp Immunol, 2008. Vol. 152(1): 138-146; cited in the IDS filed on 8/10/2023) are withdrawn in light of the claim amendment that incorporates the new limitation; However, upon further consideration, the rejection has been reapplied as necessitated by amendment for the reasons set forth herein.
Claim Interpretation
The limitation of “thereby inducing immune tolerance toward the therapeutic in the subject” in claim 1 is reasonably construed to be an intended result or outcome of the method steps positively recited.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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.
Claims 1, 23-25 and 55-58 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention (newly applied as necessitated by amendment).
Instant claim(s) broadly recites a method of inducing immune tolerance in a subject that is a human with Pompe disease in need of treatment with genus human acid alpha-glucosidase as the therapeutic, comprising administering to the subject an effective amount of methotrexate in a single cycle of the dosing regimen of the therapeutic and not in subsequent cycles of the dosing regimen, and the subject is administered the therapeutic for more than one cycle of dosing regimen. Instant claim(s) also recites the immune tolerance toward the therapeutic is assessed by measuring anti-human acid alpha-glucosidase antibody in the subject. The specification does not reasonably convey to one of ordinary skill in the art that Applicant was in possession of inducing the full scope of immune tolerance in human with Pompe disease administered with the genus human acid alpha-glucosidase for more than one cycle of dosing regimen.
According to MPEP 2163, I, B “[n]ew or amended claims which introduce elements or limitations that are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971) (subgenus range was not supported by generic disclosure and specific example within the subgenus range); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (an adequate description of a genus may not support claims to a subgenus or species within the genus)”.
In the present case, the specification only provides written basis for administering an effective amount of methotrexate in a single cycle for inducing immune tolerance in a subject in need of treatment with a therapeutic (see e.g., [0009]), such that the “single cycle” is a dosing regimen of methotrexate rather than a dosing regimen of the claimed therapeutic (human acid alpha-glucosidase). In other words, the claimed term “cycle” is only used in the context of methotrexate alone rather therapeutic (human acid alpha-glucosidase). In addition, the specification fails to provide adequate written description to support the genus dosing regimen of therapeutic, see e.g., “administered the therapeutic for more than one cycle of a dosing regimen” in the claim language.
It is respectfully noted that the disclosure does not provide adequate written description to support that the human with Pompe disease is administered the therapeutic (human acid alpha-glucosid) for more than one cycle of dosing regimen, nor provides adequate written description to support the methotrexate is administered to human with Pompe disease in a single cycle of the dosing regimen of the therapeutic (human acid alpha-glucosidase) and not in subsequent cycles of said dosing regimen. While the specification discloses “Myozyme® (recombinant human alglucosidase alpha or "rhGAA") and Lumizyme® (alglucosidase alpha) for Pompe disease” in the exemplary list of enzyme replacement therapies have been developed for patients with certain genetic diseases (see e.g., [0090]), the specification fails to provide blaze marks directing one of ordinary skill in the art to the presently claimed specific combination of
subject is a human with Pompe disease in need of treatment with human acid alpha-glucosidase as the therapeutic;
administering to the subject an effective amount of methotrexate;
the subject is administered the therapeutic for more than one cycle of a dosing regimen;
the effective amount of methotrexate is administered in a single cycle of the dosing regimen of the therapeutic;
methotrexate is not administered in subsequent cycles of the dosing regimen; and
immune tolerance toward the therapeutic is assessed by measuring anti-human acid alpha-glucosidase antibody in the subject.
The disclosure also does not provide representative of method examples thereof spanning across the claimed genus.
Therefore, the specification does not reasonably convey to one of ordinary skill in the art that Applicant was in possession of administering to a human subject with Pompe disease in need of treatment with the human acid alpha-glucosidase as a therapeutic an effective amount of methotrexate in a single cycle of a dosing regimen of human acid alpha-glucosidase, and not in subsequent cycles of the dosing regimen, and the subject is administered the therapeutic for more than one cycle of dosing regimen for inducing the full scope of immune tolerance.
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 24-25 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 (newly applied as necessitated by amendment).
Regarding claim 24-25, the limitation "the single cycle of methotrexate" lacks antecedent basis, because “a single cycle of methotrexate” is not recited prior to this recitation in the claim. It is not clear what is being referred to as the single cycle of methotrexate. Is applicant referring back to “a single cycle of the dosing regimen of the therapeutic” or simply referring to “a” single cycle of methotrexate that is not previously introduced? The lack of clarity renders the claim indefinite, because one of ordinary skill in the art cannot reasonably determine which single cycle of methotrexate is being referred to therein. In order to advance prosecution, the examiner is examining the claim to the extent that the claim(s) is drawn to a single cycle of a methotrexate rather than the single cycle of the dosing regimen of the therapeutic.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 23-25 and 55-58 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Joseph et al. (Clin Exp Immunol, 2008. Vol. 152(1): 138-146; cited in the IDS filed on 8/10/2023) (newly reapplied as necessitated by amendments).
Joseph et al. teaches recombinant human acid [Symbol font/0x61]-glucosidase (rhGAA) has been shown to be effective as an enzyme replacement therapies (ERT) for infantile-onset Pompe disease; and the majority of infantile Pompe patients treated with rhGAA developed antibodies directed against this therapeutic protein (see e.g., p. 138, right column, line 1-5). Joseph et al. further teaches several immunosuppressive agents, including methotrexate, were evaluate for their potential to induce immune tolerance to rhGAA using a mouse model of Pompe disease, which recreates the genetic deficiency observed in humans disease by deleting the endogenous expression of GAA [GAA knock out (KO)] (see e.g., abstract; p. 138, right column, last paragraph to p. 139, left column, line 11); and methotrexate (MTX) was the only agent that reduced recombinant human acid [Symbol font/0x61]-glucosidase-specific antibody response in an acid [Symbol font/0x61]-glucosidase knock-out mice (see e.g., abstract; p. 143, right column, last paragraph). Joseph et al. teaches a short course of low-dose methotrexate (MTX) treatment can induce a long-lived suppression of recombinant human acid a-glucosidase (rhGAA)-specific immunoglobulin (IgG) responses (see e.g., Fig 5); specifically, acid a-glucosidase (GAA) knock-out mice were injected weekly for 32 weeks with 20 mg/kg of recombinant human acid [Symbol font/0x61]-glucosidase (rhGAA), and 5 or 0.5 mg/kg of methotrexate was administered for either the first 3 or 8 weeks of chronic weekly rhGAA treatment; and then rhGAA-specific IgG was evaluated every other week to week 16 and then monthly to 32 weeks by serum enzyme-linked immunosorbent assay (ELISA) shown below:
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285
446
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(see e.g., Fig 5). Joseph et al. further teaches three treatments and eight treatments of 0.5 mg/kg yielded a 47% and 46% reduction in rhGAA-specific antibody levels respectively; while three
and eight treatments of 5 mg/kg generated a 66% and 65% reduction in rhGAA-specific IgG levels respectively (see e.g., p. 143, left column, “[a] short course of 0·5 mg/kg of MTX can induce a long-lived suppression of the rhGAA-specific IgG response”, 1st paragraph). Joseph et al. further teaches the work above demonstrates a distinct benefit of administering MTX within the first 24 h of rhGAA treatments. In particular, the addition of a 0 h time-point to the original 24-and 48-h weekly MTX regimen allowed MTX doses as low as 0.5 mg/kg to control rhGAA-specific immune responses successfully (see e.g., p. 143, left column, “[a] short course of 0.5 mg/kg of MTX can induce a long-lived suppression of the rhGAA-specific IgG response”, 3rd paragraph). Joseph et al. further teaches the success of this methotrexate regimen appears to require methotrexate administration within the first 24 h of recombinant human acid [Symbol font/0x61]-glucosidase treatment (see e.g., abstract). Joseph et al. further teaches a regimen of 0.5 mg/kg 3x/week represents a MTX dose (the human equivalent dose for a 5-kg 3-month-old infant would be 0.6 mg/week), which is lower than the 7.5-15 mg/week used for the treatment of juvenile and adult rheumatoid arthritis; Joseph et al. further teaches the MTX doses used to treat rheumatoid arthritis are considered generally non-toxic but can be associated with side effects (see e.g., p. 145, left column, line 31-40).
In the present case, Joseph et al. clearly teaches methotrexate induces immune tolerance to rhGAA in a mouse model of Pompe disease by administering rhGAA once a week and administering methotrexate (0.5 or 5 mg/kg) at 0, 24, and 48 h following either the initial three or eight weekly rhGAA administrations, and then evaluating rhGAA-specific IgG by serum enzyme-linked immunosorbent assay. A person of ordinary skill in the art would have understood the initial three or eight weekly administrations of rhGAA represents a discrete treatment course (i.e., a cycle) of the therapeutic (rhGAA). Therefore, Joseph et al. at least inherently teaches the administration of an effective amount of methotrexate in a cycle of rhGAA administration, and not in subsequent cycles. The difference between the method of Joseph et al. and the claimed method is that the prior art uses acid [Symbol font/0x61]-glucosidase (GAA) knock-out mice as a model of Pompe disease rather than a human with Pompe disease. It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to modify the method of Joseph et al. above by selectively choose to incorporate a human as the subject with Pompe disease in need of rhGAA in order to translate the preclinical results to clinical trials, and substituting the 0.5 mg/kg 3x/week dose of methotrexate with 0.6 mg/week for a 5-kg 3-month-old infant. Please note 0.6 mg/week for a 5 kg subject, which when calculated by
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, gives 0.12 mg/kg per week of methotrexate; and when calculated by
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, gives 0.04 mg/kg 3x/week of methotrexate. One would have been motivated to arrive at the claimed invention, because Joseph et al. teaches the GAA knock out mice used in the model of Pompe disease recreates the genetic deficiency observed in humans disease by deleting the endogenous expression of GAA; and further teaches a regimen of 0.5 mg/kg 3x/week used in said model represents a human equivalent dose of 0.6 mg/week for a 5-kg 3-month-old infant. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the same or substantially similar immune tolerance inducing effect can also be found in a human with Pompe disease when administered with a human equivalent dose of methotrexate (0.6 mg/week for 5 kg subject, which is 0.04 mg/kg for 3x/week dose) at 0, 24, and 48 hours following the initial three or eight weekly rhGAA, because it is well established in the art that therapeutic agents demonstrated effective in murine models are evaluated in human subjects for clinical application; and that renders obvious the limitation of “2 … consecutive days of methotrexate administration” in claim 24, and the limitation of “wherein the single cycle of methotrexate is administered between 48 hours prior to and 48 hours after the onset of the therapeutic treatment” in claim 25.
Regarding the limitation “the effective amount is 0.1 mg/kg to 5 mg/kg” in claim 23, to the extent that the effective amount is the effective amount of methotrexate per week, then the human equivalent dose of 0.6 mg/week methotrexate for 5 kg subject set forth above renders obvious the limitation instantly claimed. In the alternative, to the extent that the effective amount is the effective amount of methotrexate per dose, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to modify the effective amount of methotrexate in the method of Joseph et al. set forth above through routine optimization, because Joseph et al. teaches the rhGAA-specific IgG levels in the 5 mg/kg methotrexate treated mice were lower than the 0.5 mg/kg methotrexate-treated mice. One would have reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed effective amount of methotrexate, because one would have reasonably expected that the effective amount of methotrexate is a result-effective variable; and therefore, by increasing the effective amount of methotrexate starting from 0.6 mg/week for 5 kg subject, which is 0.04 mg/kg for 3x/week dose, in the method set forth above would have successfully reduce the rhGAA-specific IgG levels.
Regarding the limitation of “wherein the immune tolerance toward the therapeutic is assessed by measuring anti-human acid alpha-glycosidase antibody in the subject” in claim 1, the limitation of “measuring the anti-human acid alpha glucosidase antibody in the subject comprises measuring anti-human acid alpha-glucosidase antibody titers in a sample obtained from the subject” in claim 55, limitation of “the sample comprises serum” in claim 56, the limitation of “wherein the anti-human acid alpha-glucosidase antibody titers are anti-human acid alpha-glucosidase-specific immunoglobulin G (IgG) titers” in claim 57, and the limitation of “wherein an enzyme-linked immunosorbent assay (ELISA) is used to measure the anti-human acid alpha-glucosidase antibody” in claim 58, each of these claimed limitations is obvious by the fact that Joseph et al. teaches the rhGAA-specific IgG titer in the subject following the rhGAA treatment were measured or evaluated by serum enzyme-linked immunosorbent assay in the method set forth above. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the immune tolerance induction with methotrexate can be evaluated by measuring the recombinant human acid a-glucosidase (rhGAA)-specific immunoglobulin (IgG) titer in the human subject using the serum enzyme-linked immunosorbent assay (ELISA).
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent factual evidence to the contrary.
Response to Arguments
Applicant's arguments filed on April 16, 2026 with respect to the rejection of claims 1, 7, 11, 20, 22-25 and 54 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Joseph et al. (Clin Exp Immunol, 2008. Vol. 152(1): 138-146; cited in the IDS filed on 8/10/2023) have been fully considered but they are not persuasive.
Applicant amends independent claim 1 by deleting the recitation of “in a single cycle” and added the new limitation that recites “,wherein the subject is administered the therapeutic for more than one cycle of a dosing regimen, wherein the effective amount of methotrexate is administered in a single cycle of the dosing regimen of the therapeutic, wherein methotrexate is not administered in subsequent cycles of the dosing regimen, wherein the subject is a human with Pompe disease and the therapeutic is human acid alpha-glucosidase, wherein immune tolerance toward the therapeutic is assessed by measuring anti-human acid alpha-glucosidase antibody in the subject”. Each of these findings demonstrate that the amendment changes the scope of the claims, and necessitate a modification of the rejection on the record.
In Summary, Applicant argues the claim amendment overcomes the rejection on the record, because Joseph et al. fails to teach or suggest the newly added limitation(s) specifically drawn to administering methotrexate in a single cycle of a dosing regimen of human acid alpha-glucosidase, and not in subsequent cycles of the dosing regimen of human acid alpha-glucosidase; and the subject is administered human acid alpha-glucosidase for more than one cycle. Applicant further argues the claimed invention demonstrates unexpected mechanism of action which induces immune tolerance through induction of regulatory B cell population rather than killing proliferating cells by directing to Example 15; and further directs attention to Example 8 and 10; Fig. 15A-15C, 19-21 and 51B; and [0193] of the specification to further support the unexpected results (see page 10 of the reply).
In response, applicant’s argument is not found persuasive for the reasons set forth below:
First, applicant’s assertion that Joseph et al. fails to teach or suggest the administration of methotrexate in a single cycle of a dosing regimen of therapeutic (human acid alpha-glucosidase), and not in subsequent cycles of the dosing regimen appears is not found persuasive, because Joseph et al. clearly teaches the administration of recombinant human acid [Symbol font/0x61]-glucosidase (rhGAA) once a week and the administration of methotrexate (0.5 or 5 mg/kg) at 0, 24, and 48 h following either the initial three or eight weekly rhGAA administrations. A person of ordinary skill in the art would have understood the initial three or eight weekly administrations of rhGAA taught by Joseph et al. represents a discrete treatment course (i.e., a cycle) of the therapeutic (rhGAA). Therefore, Joseph et al. at least inherently teaches the administration of an effective amount of methotrexate in a cycle of rhGAA administration, and not in subsequent cycles of rhGAA administration.
Second, applicant’s augment that the claimed invention demonstrates unexpected mechanism of action of methotrexate (i.e., “methotrexate induces immune tolerance not by the expected means of killing proliferating cells, but rather through the specific induction of regulatory B cell populations that express TGF-beta, IL-10, and FoxP3”) is not found persuasive. It is respectfully noted that the unexpected results upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). To the extent Applicant’s position is accepted, according to MPEP 2145, II, “’[t]he fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious’. Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f))”. It is respectfully noted that products of identical or similar composition (i.e., methotrexate) cannot exert mutually exclusive properties when administered under the same or similar circumstances. Applying the same logic to the instant process claims, by practicing the method made obvious by Joseph et al. (see rejection above), one will also be inducing regulatory B cell populations that express TGF-beta, IL-10, and FoxP3 since the same compound (methotrexate) is being administered to the subject with Pompe disease, in the absence of evidence showing otherwise.
Third, applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention.
According to MPEP 716.02(d), “whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the ‘objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.’ In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
In the instant case, applicant argues the unexpected results (i.e., “methotrexate induces immune tolerance not by the expected means of killing proliferating cells, but rather through the specific induction of regulatory B cell populations”) are demonstrated in Example 8, 10 and 15; Fig. 15A-15C, 19-21 and 51B, and [0193] of the specification, respectively. Each of these disclosures have been fully considered by the Examiner. It is respectfully noted that none of these examples and figures above exemplified the administration of methotrexate to a human subject with Pompe disease or a subject with Pompe disease.
Instant claim 1 broadly recites a method of inducing immune tolerance in a subject that is a human with Pompe disease in need of treatment with a therapeutic that is human acid alpha-glucosidase, comprising administering to the subject an effective amount of methotrexate in a single cycle of the dosing regimen of the therapeutic and not in subsequent cycles of the dosing regimen, and the subject is administered the therapeutic for more than one cycle of dosing regimen; and the immune tolerance is assessed by measuring anti-human acid alpha-glucosidase antibody in the subject.
For example, Example 15 of the specification describes an adoptive transfer experiment which specifically isolates spleens from animals/mice treated with Myozyme® (recombinant human acid alpha-glucosidase) alone or with Myozyme® + methotrexate 7 days after the treatment, and then purified all of the splenic B cells; and then said splenic B cells were transferred into a naïve mice that is then treated with 20 mg/kg of Myozyme® weekly to evaluate anti-rhGAA titers (see e.g., [0193]; Figure 51A-B). The specification does not describe the effective amount of methotrexate used therein nor describe the dosing regimen of recombinant human acid alpha-glucosidase for more than one cycle in the non-naïve mice, and that does not provide adequate basis for concluding that similar results would be obtained in the full scope of effective amount of methotrexate and the full scope of dosing regimen of human acid-alpha-glucosidase for more than one cycle. The specification only demonstrate unexpected results using the splenic B cells of a mice, and that is not commensurate in scope to encompassed any cells or B cells in any sample of a human subject with Pompe disease as broadly encompassed by the claims.
Furthermore, Example 8 of the specification (see e.g., [0153]-[0154]; Figure 15A-15B; [0039]) describes animal/mice were injected weekly with 20 mg/kg i.v. rhGAA for twelve consecutive weeks, then rested for four weeks, and then re-challenge with rhGAA at week 16; the animals were also given a single cycle of three consecutive daily doses of 5 mg/kg methotrexate at week 1, or given one cycle at each of weeks 1, 2, and 3 (with a total of three cycles), in which the group that received 1 cycle of methotrexate experienced 77% reduction in average anti-myozyme IgG titer whereas the group that received 3 cycles of methotrexate experienced 69% reduction with no statistical difference in between the two groups (see Figure 15A). The specification does not describe the animal/mice employed therein is a subject with Pompe disease nor is a human with Pompe disease. It is noted that the unexpected results upon which applicant relies (i.e., “methotrexate induces immune tolerance not by the expected means of killing proliferating cells, but rather through the specific induction of regulatory B cell populations”) is not described in Example 8, because said example only measure the anti-human acid alpha-glucosidase-specific IgG titers rather than regulatory B cells. To the extent applicant is referring “reducing anti-drug antibodies against human acid alpha-glucosidase” as an unexpected results, said unexpected result is only exemplified using a single regimen species of rhGAA (20 mg/kg i.v. rhGAA for twelve consecutive weeks, then rested for four weeks, and then re-challenge with rhGAA at week 16) and a single regimen species of methotrexate (single cycle of three consecutive daily doses of 5 mg/kg methotrexate at week 1) for one cycle or three cycles in a single subject species (mice), and that does not provide adequate basis for concluding that similar results would be obtained in the full scope of human subject with Pompe disease treated with the broad scope of human acid alpha-glucosidase for more than one cycle of a broad dosing regimen; nor it provides adequate basis for concluding that similar results would be obtained when administering the full scope of effective amount of methotrexate administered in a single cycle of the dosing regimen of the human acid alpha-glucosidase, and not administered in subsequent cycles of the dosing regimen.
In short, Example 8 only exemplifies a single dosing regimen of rhGAA, and a single effective amount of methotrexate for inducing immune tolerance in mice, and that is not commensurate in scope to broadly encompass any dosing regimen of rhGAA for more than one cycle, and any effective amount of methotrexate administered in a single cycle of the dosing regimen of rhGAA for inducing immune tolerance in any human with Pompe disease.
Additionally, applicant further relies on Example 10 to support the unexpected results. According to Example 10 of the specification, it describes Myozyme® treatment (recombinant human acid alpha-glucosidase) significantly increases in the B 10 regulatory B cell population in spleen seven and eight days following the treatment in animals/mice, wherein the mice were treated with rhGAA alone or rhGAA and a single three-day cycle of the methotrexate or saline (see e.g., [0043];[0158]; Fig. 19). In addition, Fig 20 describes the absolute cell numbers of CD86+ transitional 2 B cells, CD86+ transitional 3 B cells, CD86+ follicular B cells, and CD86+ marginal zone B cells are increased on day 6 of the study; and Figure 21 demonstrated these B cells subpopuloation remain increase in two cycles of Myozyme® (administered days 1 and 8) and methotrexate (5 mg/kg given on days 1-3 and 8-10). The specification does not describe the dosing regimen of recombinant human alglucosidase alpha employed in said example, thus, the disclosure does not provide adequate basis for concluding that similar results would be obtained in the full scope of dosing regimen of human acid alpha-glucosidase for more than one cycle. The specification also does not describe the effective amount of methotrexate in Figure 19-20, aside from a disclosures that states 5 mg/kg of methotrexate was given on days 1-3 and 8-10 in Figure 21; and that single regimen species of methotrexate (5 mg/kg on days 1-3 and 8-10) also does not provide adequate basis for concluding that similar results would be obtained when administering other effective amount of methotrexate. Applicant only demonstrate unexpected results using the B 10 regulatory B cell population in spleen, CD86+ transitional 2 B cells, CD86+ transitional 3 B cells, CD86+ follicular B cells, and CD86+ marginal zone B cells obtained from mice, and is not commensurate in scope to include any cells or B cells in any sample of a human subject with Pompe disease as broadly encompassed by the claims.
In view of the foregoing, each of these findings demonstrate that the unexpected induction of regulatory B cell populations caused by methotrexate upon which applicant relies is not commensurate in scope with the claimed invention, thus, the argument is not found persuasive.
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, 23-25 and 55-58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,672,802 В2 (referred to herein as reference patent), in view of Joseph et al. (Clin Exp Immunol, 2008. Vol. 152(1): 138-146; cited in the IDS filed on 8/10/2023) (newly reapplied as necessitated by amendments).
Although the claims of the reference patent is drawn to a method of increasing the percentage of B regulatory cells in the B cell population rather than the claimed inducing immune tolerance in the subject in need of treatment with the same therapeutic, said method comprises the same active step(s) of administering to the subject an effective amount of methotrexate, wherein the subject is administered a therapeutic for more than one cycle of a dosing regimen, wherein the therapeutic is human acid alpha-glucosidase, wherein the effective amount of methotrexate is administered in a single cycle of the dosing regimen of the therapeutic, and wherein methotrexate is not administered in subsequent cycles of the dosing regimen of the therapeutic (see claim 1); wherein the effective amount of methotrexate is 0.1 mg/kg to 5 mg/kg (see claim 2); wherein the single cycle of methotrexate is administered between 48 hours prior to and 48 hours after the onset of the therapeutic treatment (see claim 3).
The reference patent does not teach the subject is a human with Pompe disease as claimed in claim 1. The reference patent also does not teach immune tolerance toward the therapeutic is assessed by measuring anti-human acid alpha-glucosidase antibody in the subject as claimed in claim 1; measuring the anti-human acid alpha-glucosidase in the subject comprises measuring anti-human acid alpha-glucosidase antibody titers in a sample obtained from the subject in claim 55; the sample comprises serum in claim 56; the anti-human acid alpha-glucosidase antibody titers are anti-human acid alpha-glucosidase-specific immunoglobulin G (IgG) titers in claim 57; and an enzyme-linked immunosorbent assay (ELISA) is used to measure the anti-human acid alpha-glucosidase antibody in claim 58. The reference patent does not teach a single cycle of methotrexate consists of 1 day of methotrexate administration or 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 consecutive days of methotrexate administration as claimed in claim 24.
Joseph et al. teaches recombinant human acid [Symbol font/0x61]-glucosidase (rhGAA) has been shown to be effective as an enzyme replacement therapies (ERT) for infantile-onset Pompe disease; and the majority of infantile Pompe patients treated with rhGAA developed antibodies directed against this therapeutic protein (see e.g., p. 138, right column, line 1-5). Joseph et al. further teaches several immunosuppressive agents, including methotrexate, were evaluate for their potential to induce immune tolerance to rhGAA using a mouse model of Pompe disease, which recreates the genetic deficiency observed in humans disease by deleting the endogenous expression of GAA [GAA knock out (KO)] (see e.g., abstract; p. 138, right column, last paragraph to p. 139, left column, line 11); and methotrexate (MTX) was the only agent that reduced recombinant human acid [Symbol font/0x61]-glucosidase-specific antibody response in an acid [Symbol font/0x61]-glucosidase knock-out mice (see e.g., abstract; p. 143, right column, last paragraph). Joseph et al. teaches a short course of low-dose methotrexate (MTX) treatment can induce a long-lived suppression of recombinant human acid a-glucosidase (rhGAA)-specific immunoglobulin (IgG) responses (see e.g., Fig 5); specifically, acid a-glucosidase (GAA) knock-out mice were injected weekly for 32 weeks with 20 mg/kg of recombinant human acid [Symbol font/0x61]-glucosidase (rhGAA), and 5 or 0.5 mg/kg of methotrexate was administered for either the first 3 or 8 weeks of chronic weekly rhGAA treatment; and then rhGAA-specific IgG was evaluated every other week to week 16 and then monthly to 32 weeks by serum enzyme-linked immunosorbent assay (ELISA) shown below:
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285
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(see e.g., Fig 5). Joseph et al. further teaches three treatments and eight treatments of 0.5 mg/kg yielded a 47% and 46% reduction in rhGAA-specific antibody levels respectively; while three
and eight treatments of 5 mg/kg generated a 66% and 65% reduction in rhGAA-specific IgG levels respectively (see e.g., p. 143, left column, “[a] short course of 0·5 mg/kg of MTX can induce a long-lived suppression of the rhGAA-specific IgG response”, 1st paragraph). Joseph et al. further teaches the work above demonstrates a distinct benefit of administering MTX within the first 24 h of rhGAA treatments. In particular, the addition of a 0 h time-point to the original 24-and 48-h weekly MTX regimen allowed MTX doses as low as 0.5 mg/kg to control rhGAA-specific immune responses successfully (see e.g., p. 143, left column, “[a] short course of 0.5 mg/kg of MTX can induce a long-lived suppression of the rhGAA-specific IgG response”, 3rd paragraph). Joseph et al. further teaches the success of this methotrexate regimen appears to require methotrexate administration within the first 24 h of recombinant human acid [Symbol font/0x61]-glucosidase treatment (see e.g., abstract). Joseph et al. further teaches a regimen of 0.5 mg/kg 3x/week represents a MTX dose (the human equivalent dose for a 5-kg 3-month-old infant would be 0.6 mg/week), which is lower than the 7.5-15 mg/week used for the treatment of juvenile and adult rheumatoid arthritis; Joseph et al. further teaches the MTX doses used to treat rheumatoid arthritis are considered generally non-toxic but can be associated with side effects (see e.g., p. 145, left column, line 31-40).
In this case, the claims of the reference patent is silent regarding the limitation of “inducing immune tolerance”. However, the reference patent practices the same method step(s) in the patient in need of the treatment of the same therapeutic (human acid alpha-glucosidase). The difference between the reference patent and the instant application is that the reference patent does not teach measuring anti-human acid alpha-glucosidase antibody in the subject nor expressly teach the subject is a human with Pompe disease. It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to selectively choose to incorporate the human with Pompe disease as the subject in need of treatment with human acid [Symbol font/0x61]-glucosidase, and then measure rhGAA-specific IgG by serum enzyme-linked immunosorbent assay (ELISA) as taught by Joseph et al. in order to translate the preclinical results to clinical trials. One would have been motivated to do so, because Joseph et al. teaches the subject treated with recombinant human acid alpha-glucosidase (rhGAA) develops antibodies directed against this therapeutic, and measuring rhGAA-specific IgG by serum enzyme-linked immunosorbent assay (ELISA) can evaluate the immune tolerance or suppression of rhGAA-specific IgG induced by methotrexate; teaches a methotrexate regimen of 0.5 mg/kg 3x/week that demonstrate efficacy in inducing immune tolerance in murine model of pompe disease represents a human equivalent dose of 0.6 mg/week for a 5-kg 3-month-old infant; and further teaches that the immunosuppressive agents, including methotrexate, can potentially antagonize the development of antibody responses either by interfering with T cell-dependent and/or T cell-independent B cell activation and differentiation. Please note 0.6 mg/week for a 5 kg subject, which when calculated by
0.6
m
g
/
w
e
e
k
÷
5
k
g
=
0.12
m
g
/
k
g
, gives 0.12 mg/kg per week of methotrexate; and when calculated by
0.6
m
g
/
w
e
e
k
÷
5
k
g
÷
3
t
i
m
e
s
/
w
e
e
k
=
0.04
m
g
/
k
g
, gives 0.04 mg/kg 3x/week of methotrexate. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected by practicing the same active steps, which administers the same methotrexate, at 0.12 mg/kg per week (for a 5 kg subject) in a human with Pompe disease as the subject in need of the treatment of human acid alpha-glucosidase would exhibits the same or substantially similar effects of increasing percentage of B regulatory cells, and inducing immune tolerance by reducing rhGAA-specific IgG titers measured by serum enzyme-linked immunosorbent assay.
Regarding the limitation of “wherein the single cycle of methotrexate consists of 1 day of methotrexate administration or 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 consecutive days of methotrexate administration” in claim 24, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the modified method of the reference patent and Joseph et al. set forth above by administering the methotrexate in a single cycle of 2 consecutive days. One would have been motivated to do so, because Joseph et al. teaches the administration of methotrexate at 0, 24, and 48 hours that includes the addition of a 0 h time-point allowed MTX doses as low as 0.5 mg/kg to control rhGAA-specific immune responses successfully. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by administering the effective amount of methotrexate treatment in 2 consecutive days (48 hours) would have successfully controlled the rhGAA-specific immune responses.
Regarding the limitation “the effective amount is 0.1 mg/kg to 5 mg/kg” in claim 23, to the extent that the effective amount is the effective amount of methotrexate per week, then the human equivalent dose of 0.6 mg/week methotrexate for 5 kg subject set forth above (equivalent to 0.12 mg/kg per week of methotrexate) renders obvious the limitation instantly claimed. In the alternative, to the extent that the effective amount is the effective amount of methotrexate per dose, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to modify the effective amount of methotrexate in the method of reference patent and Joseph et al. set forth above through routine optimization, because Joseph et al. teaches the rhGAA-specific IgG levels in the 5 mg/kg methotrexate treated mice were lower than the 0.5 mg/kg methotrexate-treated mice. One would have reasonable expectation of success to arrive at the claimed invention, including the claimed effective amount of methotrexate, because one would have reasonably expected that the effective amount of methotrexate is a result-effective variable; and therefore, by increasing the effective amount of methotrexate starting from 0.6 mg/week for 5 kg subject, which is 0.04 mg/kg for 3x/week dose, in the method set forth above would have successfully reduce the rhGAA-specific IgG levels.
Therefore, the nonstatutory double patenting rejection applies.
Response to Arguments
Applicant's arguments filed on April 16, 2026 with respect to the rejection of claims 1, 7, 11, 20, 22-25 and 54 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,672,802 В2 (referred to herein as reference patent), in view of Joseph et al. (Clin Exp Immunol, 2008. Vol. 152(1): 138-146; cited in the IDS filed on 8/10/2023) have been fully considered but they are not persuasive.
Applicant amends independent claim 1 by deleting the recitation of “in a single cycle” and added the new limitation that recites “,wherein the subject is administered the therapeutic for more than one cycle of a dosing regimen, wherein the effective amount of methotrexate is administered in a single cycle of the dosing regimen of the therapeutic, wherein methotrexate is not administered in subsequent cycles of the dosing regimen, wherein the subject is a human with Pompe disease and the therapeutic is human acid alpha-glucosidase, wherein immune tolerance toward the therapeutic is assessed by measuring anti-human acid alpha-glucosidase antibody in the subject”. Each of these findings demonstrate that the amendment changes the scope of the claims, and necessitate a modification of the rejection on the record.
In Summary, Applicant argues the amendment to the claims overcomes the nonstatutory double patenting rejection on the record. Applicant further argues the claims of the reference patent do not recite “[a]method of inducing immune tolerance in a subject in need of treatment with a therapeutic” nor “wherein immune tolerance toward the therapeutic is assessed by measuring anti-human acid
alpha-glucosidase antibody in the subject", as required by instant claim(s) after amendments. Applicant further argues Joseph et al. fails to teach “measuring anti-human acid alpha-glucosidase antibody in the subject" when "increasing the percentage of B regulatory cells in the B cell population” as required by reference claims(s) of the reference patent; therefore, the reference patent in view of Joseph et al. is considered patentably distinct.
In response, applicant’s argument is not found persuasive. Applicant’s argument towards the reference patent and Joseph et al., respectively, are against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It may well be true the reference patent does not teach measuring anti-human acid alpha-glucosidase antibody in the subject to assess immune tolerance or suppression of said antibody induced by methotrexate; However, the rejection on the record does not rely on the reference patent alone, but uses the combination of references, i.e., the reference patent and Joseph et al. It is respectfully noted that the nonstatutory double patenting rejection on the record further rely on Joseph et al. to establish the subject treated with recombinant human acid [Symbol font/0x61]-glucosidase (rhGAA) develops therapy-specific antibodies (see e.g., abstract; p. 138, right column, line 1-5), and said antibodies, e.g., rhGAA-specific IgG, can be evaluated or measured by serum enzyme-linked immunosorbent assay (ELISA) (see e.g., Fig 5); and further teaches administration of immunosuppressive agent, methotrexate, could potentially antagonize the development of antibody responses either by interfering with T cell-dependent and/or T cell-independent B cell activation and differentiation (see e.g., p. 140, right column, last paragraph); and the methotrexate can induce immune tolerance toward rhGAA by suppressing rhGAA-specific IgG response (see e.g., p. 143, left column, 1st paragraph).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the fact that Joseph et al. teaches the subject treated with recombinant human acid [Symbol font/0x61]-glucosidase (rhGAA) develops therapy-specific antibodies, e.g., rhGAA-specific IgG, that can be evaluated or measured by serum enzyme-linked immunosorbent assay (ELISA); and said antibodies can be suppressed by methotrexate (see e.g., abstract; Fig 5). In view of the teachings of Joseph et al., a ordinary skill in the art would have reasonably measure the rhGAA-specific IgG titers in the subjected treated with human acid [Symbol font/0x61]-glucosidase and methotrexate in the method of reference patent.
Claims 1, 23-25 and 55-58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5 and 12-15 of U.S. Patent No. 12,213,979 B2 (referred to herein as reference patent), in view of Joseph et al. (Clin Exp Immunol, 2008. Vol. 152(1): 138-146; cited in the IDS filed on 8/10/2023) (newly reapplied as necessitated by amendments).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference patent is drawn to a method for treating Pompe disease in a subject in need of treatment with human acid [Symbol font/0x61]-glucosidase, comprising administering to the subject an effective amount of methotrexate, and administering to the subject an effective amount of human acid [Symbol font/0x61]-glucosidase (see claim 1); wherein the effective amount of methotrexate is administered in a single cycle or in three cycles (see claim 5); wherein a cycle of methotrexate consists of 1 day of methotrexate administration or 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 consecutive days of methotrexate administration (see claim 12); wherein the methotrexate is administered between 48 hours prior to and 48 hours after administration of human acid [Symbol font/0x61]-glucosidase (see claims 13-14); wherein the methotrexate is administered at about 0.1 mg/kg to about 5 mg/kg (see claim 15).
The reference patent does not teach the subject is a human as claimed in claim 1. The reference patent also does not teach immune tolerance toward the therapeutic is assessed by measuring anti-human acid alpha-glucosidase antibody in the subject as claimed in claim 1; measuring the anti-human acid alpha-glucosidase in the subject comprises measuring anti-human acid alpha-glucosidase antibody titers in a sample obtained from the subject in claim 55; the sample comprises serum in claim 56; the anti-human acid alpha-glucosidase antibody titers are anti-human acid alpha-glucosidase-specific immunoglobulin G (IgG) titers in claim 57; and an enzyme-linked immunosorbent assay (ELISA) is used to measure the anti-human acid alpha-glucosidase antibody in claim 58.
Joseph et al. teaches recombinant human acid [Symbol font/0x61]-glucosidase (rhGAA) has been shown to be effective as an enzyme replacement therapies (ERT) for infantile-onset Pompe disease; and the majority of infantile Pompe patients treated with rhGAA developed antibodies directed against this therapeutic protein (see e.g., p. 138, right column, line 1-5). Joseph et al. further teaches several immunosuppressive agents, including methotrexate, were evaluate for their potential to induce immune tolerance to rhGAA using a mouse model of Pompe disease, which recreates the genetic deficiency observed in humans disease by deleting the endogenous expression of GAA [GAA knock out (KO)] (see e.g., abstract; p. 138, right column, last paragraph to p. 139, left column, line 11); and methotrexate (MTX) was the only agent that reduced recombinant human acid [Symbol font/0x61]-glucosidase-specific antibody response in an acid [Symbol font/0x61]-glucosidase knock-out mice (see e.g., abstract; p. 143, right column, last paragraph). Joseph et al. teaches a short course of low-dose methotrexate (MTX) treatment can induce a long-lived suppression of recombinant human acid a-glucosidase (rhGAA)-specific immunoglobulin (IgG) responses (see e.g., Fig 5); specifically, acid a-glucosidase (GAA) knock-out mice were injected weekly for 32 weeks with 20 mg/kg of recombinant human acid [Symbol font/0x61]-glucosidase (rhGAA), and 5 or 0.5 mg/kg of methotrexate was administered for either the first 3 or 8 weeks of chronic weekly rhGAA treatment; and then rhGAA-specific IgG was evaluated every other week to week 16 and then monthly to 32 weeks by serum enzyme-linked immunosorbent assay (ELISA) shown below:
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285
446
media_image1.png
Greyscale
(see e.g., Fig 5). Joseph et al. further teaches three treatments and eight treatments of 0.5 mg/kg yielded a 47% and 46% reduction in rhGAA-specific antibody levels respectively; while three
and eight treatments of 5 mg/kg generated a 66% and 65% reduction in rhGAA-specific IgG levels respectively (see e.g., p. 143, left column, “[a] short course of 0·5 mg/kg of MTX can induce a long-lived suppression of the rhGAA-specific IgG response”, 1st paragraph). Joseph et al. further teaches the work above demonstrates a distinct benefit of administering MTX within the first 24 h of rhGAA treatments. In particular, the addition of a 0 h time-point to the original 24-and 48-h weekly MTX regimen allowed MTX doses as low as 0.5 mg/kg to control rhGAA-specific immune responses successfully (see e.g., p. 143, left column, “[a] short course of 0.5 mg/kg of MTX can induce a long-lived suppression of the rhGAA-specific IgG response”, 3rd paragraph). Joseph et al. further teaches the success of this methotrexate regimen appears to require methotrexate administration within the first 24 h of recombinant human acid [Symbol font/0x61]-glucosidase treatment (see e.g., abstract). Joseph et al. further teaches a regimen of 0.5 mg/kg 3x/week represents a MTX dose (the human equivalent dose for a 5-kg 3-month-old infant would be 0.6 mg/week), which is lower than the 7.5-15 mg/week used for the treatment of juvenile and adult rheumatoid arthritis; Joseph et al. further teaches the MTX doses used to treat rheumatoid arthritis are considered generally non-toxic but can be associated with side effects (see e.g., p. 145, left column, line 31-40).
In this case, the claims of the reference patent is silent regarding the limitation of “inducing immune tolerance”. However, the reference patent administer the same effective amount of methotrexate to the patient with Pompe disease in need of the treatment of the same therapeutic (human acid alpha-glucosidase). The difference between the reference patent and the instant application is that the reference patent does not expressly teach the subject is a human, and the reference patent also does not teach administering the effective amount of methotrexate in a single cycle of the dosing regimen of the therapeutic, and not in subsequent cycles of the dosing regimen; and measuring anti-human acid alpha-glucosidase antibody in the subject nor expressly teach. It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to selectively choose to incorporate human as a subject with Pompe disease in need of treatment with human acid [Symbol font/0x61]-glucosidase in order to translate the preclinical results to clinical trials, and then administering the effective amount of the methotrexate at 0, 24, and 48 h following either the initial three or eight weekly human acid [Symbol font/0x61]-glucosidase administrations, and then evaluating human acid [Symbol font/0x61]-glucosidase-specific IgG by serum enzyme-linked immunosorbent assay as taught by Joseph et al. One would have been motivated to do so, because Joseph et al. teaches the subject treated with recombinant human acid alpha-glucosidase (rhGAA) develops antibodies directed against this therapeutic, and measuring rhGAA-specific IgG by serum enzyme-linked immunosorbent assay (ELISA) can evaluate the immune tolerance or suppression of rhGAA-specific IgG induced by methotrexate; and teaches the methotrexate given at 0, 24, and 48 h following either the initial three or eight weekly rhGAA administration can induce a long-lived suppression of rhGAA-specific IgG response. A person of ordinary skill in the art would have understood the initial three or eight weekly administrations of rhGAA represents a discrete treatment course (i.e., a cycle) of the therapeutic (rhGAA). Therefore, Joseph et al. at least inherently teaches the administration of an effective amount of methotrexate in a cycle of rhGAA administration, and not in subsequent cycles. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected by administering an effective amount of methotrexate to a human with Pompe disease at 0, 24, and 48 h following either the initial three or eight weekly rhGAA administration would exhibits the same or substantially similar effects of treating Pompe disease while inducing immune tolerance towards human acid [Symbol font/0x61]-glucosidase by reducing human acid [Symbol font/0x61]-glucosidase-specific IgG titers measured by serum enzyme-linked immunosorbent assay.
Therefore, the nonstatutory double patenting rejection applies.
Response to Arguments
Applicant's arguments filed on April 16, 2026 with respect to the rejection of claims 1, 7, 11, 20, 22-25 and 54 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 12-15 of U.S. Patent No. 12,213,979 B2 (referred to herein as reference patent), in view of Joseph et al. (Clin Exp Immunol, 2008. Vol. 152(1): 138-146; cited in the IDS filed on 8/10/2023) have been fully considered but they are not persuasive.
Applicant amends independent claim 1 by deleting the recitation of “in a single cycle” and added the new limitation that recites “,wherein the subject is administered the therapeutic for more than one cycle of a dosing regimen, wherein the effective amount of methotrexate is administered in a single cycle of the dosing regimen of the therapeutic, wherein methotrexate is not administered in subsequent cycles of the dosing regimen, wherein the subject is a human with Pompe disease and the therapeutic is human acid alpha-glucosidase, wherein immune tolerance toward the therapeutic is assessed by measuring anti-human acid alpha-glucosidase antibody in the subject”. Each of these findings demonstrate that the amendment changes the scope of the claims, and necessitate a modification of the rejection on the record.
In Summary, applicant argues the reference patent is not a proper reference for nonstatutory double patenting rejection, because the instant application has earlier effective filing date.
In response, Applicant’s argument is not persuasive. Applicant’s assertion that the nonstatutory double patenting rejection is not proper based on the later effective filing date of reference patent is not true, because “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 MPEP 804, II, B with regard to Nonstatutory Double Patenting. Since the conflicting claims of the reference patent in view of Joseph et al. renders obvious the claimed invention, the nonstatutory double patenting rejection is considered proper.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chihyi Lee whose telephone number is (571)270-0663. The examiner can normally be reached Monday - Friday 8:30 am - 5:00 pm EST.
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, Amy L. Clark can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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