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
in the reply filed on November 10, 2025 is acknowledged.
Claims 12-19 and 21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 10, 2025.
Status of Claims
Claims 1, 7, 11-25, and 54 are pending. Claims 12-19 and 21 are withdrawn.
Claims 1, 7, 11, 20, 22-25 and 54 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 statements (IDS) submitted on 8/10/2023 and 11/10/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The information disclosure statement filed on August 10, 2023 appears to have identical citations to the information disclosure statements in the parent case of U.S. Patent Application No. 16/828,407 filed on March 24, 2020 unless otherwise noted. According to MPEP § 609.2 with regard to information disclosure statements in continued examination or continuing application, the Examiner of the continuing application would consider information which has been considered by the office in the parent application. As such, while the legible copy of each cited foreign patent document and each non-patent literature publication has not been provided by the Applicants in this instant application, the information disclosure has been considered by the Examiner.
Dilillo et al. (cited under “Non-Patent Literature Documents”, no. 35 in IDS filed on August 10, 2023), Jolivet et al. (cited under “Non-Patent Literature Documents”, no. 45 in IDS filed on August 10, 2023), Khouri et al. (cited under “Non-Patent Literature Documents”, no. 49 in IDS filed on August 10, 2023), sYANABA et al. (cited under “Non-Patent Literature Documents”, no. 80 in IDS filed on August 10, 2023) do not have a legible copy in the application file nor in the parent case. Thus, while the references have been cited in the IDS filed on August 10, 2023, the documents have not been considered by the Examiner.
Please note the foreign references without an English translation but have an English translation of the abstract will only have the abstract considered by the Examiner.
Specification
The disclosure is objected to because of the following informalities:
The use of the terms “Thymoglobulin®” and “Myozyme®”, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
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, 7, 11, 20, 22-25 and 54 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for inducing immune tolerance in a Pompe disease subject in need of treatment with human acid alpha-glucosidase, a multiple sclerosis subject in need of treatment with alemtuzumab, and a subject with solid organ transplantation in need of treatment with anti-thymocyte globulin polyclonal antibody, does not reasonably provide enablement for administering any effective amount of methotrexate in a single cycle to any subject in need of treatment with the entire scope of therapeutic for inducing immune tolerance. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and, (8) the quantity of experimentation necessary. All of the Wands factors have been considered and discussed below:
(1, 5) The breadth of the claims and the Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
In the instant case, claim 1 recites “A method of inducing immune tolerance in a subject in need of treatment with a therapeutic, comprising administering to the subject an effective amount of methotrexate in a single cycle, thereby inducing immune tolerance toward the therapeutic in the subject”.
The claimed term “therapeutic”, when given its broadest reasonable interpretation, is taken to include a wide variety of biological therapies, such as protein therapeutics and enzyme replacement therapeutics.
Therefore, the breadth of the claims cover the administration of any effective amount of methotrexate in a single cycle for inducing immune tolerance in any subject in need of treatment with any therapeutic.
(2, 3, 4) The state of the prior art, the level of skill in the art, and the predictability or lack
thereof in the art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the
art would have known, at the time the application was filed, about the subject matter to which the
claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art
refers to the skill of those in the art in relation to the subject matter to which the claimed invention
pertains at the time the application was filed.”
As discussed above, the claimed invention pertains to a method of inducing immune tolerance in any subject in need of treatment with each and every therapeutic species comprising administering to the subject any effective amount of methotrexate in a single cycle.
At the time the invention was made, one skilled in the art would have known that the administration of methotrexate to the murine model of Pompe disease at 0, 24 and 48 h following the initial three or eight weekly human acid [Symbol font/0x61]-glucosidase (rhGAA) administrations can successfully induce immune tolerance induction to said enzyme-replacement therapy, as evidenced by Joseph et al. (Clin Exp Immunol, 2008. Vol. 152(1): 138-146; cited in the IDS filed on 8/10/2023).
According to Ghosh et al. (Mol Ther Methods Clin Dev, 2019. Vol. 13: 321-333), even though low-dose, short-course methotrexate monotherapy was shown to prevent antibody responses to recombinant human a-glucosidase in a Pompe mouse model (see e.g., p. 322, left column, 3rd paragraph), immune tolerance induction with methotrexate does not appear to be effective in mucopolysaccharidosis type I patients treated with laronidase as the enzyme replacement therapy (see e.g., abstract; p. 323, left column, “Anti-laronidase IgG Antibodies, IgM Antibodies, and Cellular Uptake Inhibition in MPS I Patients Treated with Methotrexate”). Ghosh et al. further teaches the participants received either 1 or 3 cycles of methotrexate; and each cycle comprised a series of 3 doses of oral methotrexate, given at 0.4 mg/kg/dose 60 min before laronidase infusion, 24 h after infusion, and 48 h after infusion (see e.g., p. 329, left column, first paragraph under “Methotrexate Monotherapy in MPS IH Patients: Immune Tolerance Induction with Methotrexate in Hurler Syndrome Trial Design”). In other words, the cited reference demonstrates methotrexate monotherapy does not necessarily induce immune tolerance in any subject in need of treatment with therapeutic, including mucopolysaccharidosis type I patients treated with laronidase as the therapeutic; therefore, the state of the art with respect to administering any effective amount of methotrexate in a single cycle for inducing immune tolerance in any subject in need of treatment with each and every therapeutic is still undeveloped due to the unpredictability surrounding immune tolerance induction.
In the present case, even though Applicant’s claimed methotrexate may play a role in a method of inducing immune tolerance in a subject with Pompe disease in need of treatment with human acid alpha-glucosidase, a multiple sclerosis subject in need of treatment with alemtuzumab, and a subject with solid organ transplantation in need of treatment with anti-thymocyte globulin polyclonal antibody, it is uncertain whether the administration of any effective amount of methotrexate in a single cycle can successfully induce immune tolerance in any subject in need of treatment with each and every therapeutic based on the unpredictability of immune tolerance induction.
(6, 7, 8) The amount of guidance given, the presence of working example and the quantitation
of experimentation required:
In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the claimed invention. In the present case, the specification discloses 5 mg/kg of methotrexate administered intraperitoneally to normal female C57BL/6 mice for six consecutive days starting on the first of two murine anti-thymocyte globulin (mATG) administrations (25mg/kg, 3 days apart) or on the first of five monthly mATG treatments (five monthly injections of mATG at 5 mg/kg/injection) could suppress anti-mATG IgG responses (see Example 2; [0110]). The specification further discloses 0.5, 1 or 5 mg/kg of methotrexate administered to human CD52 (huCD52) transgenic mice at 15 minutes prior to the first monthly alemtuzumab dose as well as 24 and 48 hours after the dose, in which 1 mg/kg of methotrexate provides some benefits and 5 mg/kg of methotrexate successfully reduced anti-alemtuzumab IgG responses (see Example 4; [0110]). The specification further discloses the mice treated with rhGAA (20 mg/kg of rhGAA by bolus tail vein injection) received a single cycle of three consecutive daily dose of 5 mg/kg methotrexate at week 1 shows little to no ADA (see Example 8; [0113]). In summary, the specification only exemplifies the administration of methotrexate to a mice subject treated with mATG, alemtuzumab or rhGAA as the therapeutic. Therefore, the quantity of experimentation necessary to carry out the claimed invention is high, because one of the relative skill in the art could not reasonably predict which subject needing therapeutic treatment encompassed by the claims will successfully develop immune tolerance after the administration of methotrexate at any effective amount in a single cycle based on the limited disclosure provided; Therefore, it would require undue experimentations as it is highly unpredictable that the administration any effective amount of methotrexate in a single cycle would, in fact, be usable across the entire scope of subject in need of treatment with each and every therapeutic for inducing immune tolerance.
Accordingly, the method of inducing immune tolerance in any subject in need of treatment with each and every therapeutic, comprising administering to the subject any effective amount of methotrexate in a single cycle is not enabled by the instant specification. To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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 the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claims 1, 7, 20, 22-25 and 54 are 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).
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). Joseph et al. further teaches 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. further teaches the success of this methotrexate regimen appears to require methotrexate administration within the first 24 h of recombinant human acid a-glucosidase treatment (see e.g., abstract); 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, last paragraph). Joseph et al. further teaches methotrexate was administered i.p. 0, 24 and 48 h following the initial three or eight weekly rhGAA administrations; and the dose range of MTX tested was 0.5-50 mg/kg (see e.g., p. 139, right column, 2nd paragraph). Joseph et al. further teaches 5 or 0.5 mg/kg of MTX was administered for either the first 3 or 8 weeks of chronic weekly rhGAA treatment shown below:
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(see e.g., Fig. 5).
In the present case, Joseph et al. clearly teaches a method of inducing immune tolerance to rhGAA by administering 0.5-50 mg/kg of methotrexate to the GAA knock out mice in the model of Pompe disease at 0, 24, and 48 hours following the initial three or eight weekly rhGAA, and said GAA knock out mice is a subject in need of treatment with the elected therapeutic and a Pompe disease patient; and said methotrexate administration at 0, 24, and 48 hours is considered a single cycle. Please note the rhGAA of Joseph et al. is a protein therapeutic and an enzyme.
Regarding the limitation of “wherein the effective amount is 0.1 mg/kg to 5 mg/kg” in claim 23 , the limitation of “wherein the single cycle of methotrexate consist 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, 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, “[w]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art.” Titanium Metals Corp.v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). In the present case, Joseph et al. clearly teaches the administration of 0.5 mg/kg of methotrexate at 0, 24, and 48 hours following the initial three or eight weekly rhGAA. The 0.5 mg/kg of methotrexate taught by Joseph et al. is an effective amount and the administration at 0, 24, and 48 hours is a single cycle of methotrexate consist of 2 consecutive days (48 hours), which is within 48 hours after the onset of the therapeutic treatment as it is given immediately after (0 hour) the administration of rhGAA.
Therefore, the claimed invention is being anticipated by Joseph et al.
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, 7, 11, 20, 22-25 and 54 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).
The teachings of Joseph et al. are set forth above and applied as before.
Joseph et al. does not teach the subject is a human as claimed in claim 11.
In addition to the teachings set forth above, Joseph et al. further teaches a regimen of 0.5 mg/kg 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).
The difference between the method of Joseph et al. and the claimed method is that the prior art administers the methotrexate to the GAA knock out mice in the model of Pompe disease rather than a human instantly claimed. 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. by administering 0.5 mg/kg of methotrexate to a human with Pompe disease at 0, 24, and 48 hours following the initial three or eight weekly rhGAA. One would have been motivated to do so, 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 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 dose used to treat rheumatoid arthritis that is generally considered non-toxic. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of 0.5 mg/kg of methotrexate to a human with Pompe disease at 0, 24, and 48 hours following the initial three or eight weekly rhGAA would successfully induce immune tolerance to rhGAA and minimize toxicities.
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.
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, 7, 11, 20, 22-25 and 54 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).
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 in a subject in need of treatment with human acid alpha-glucosidase as the therapeutic rather than inducing immune tolerance, said method comprises the same active step of administering to the subject an effective amount of methotrexate in a single cycle 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 human as claimed in claim 11. The reference patent does not teach 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 as claimed in claim 24. The reference patent does not teach the subject is a Pompe disease patient as claimed in claim 54. 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 (see e.g., p. 138, right column, 1st paragraph). Joseph et al. further teaches 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), which is a mouse model of Pompe disease that recreates the genetic deficiency observed in humans disease by deleting the endogenous expression of GAA (see e.g., p. 138, right column, last paragraph to p. 139, left column, line 11). Joseph et al. further teaches 5 or 0.5 mg/kg of MTX was administered for either the first 3 or 8 weeks of chronic weekly rhGAA treatment shown below:
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(see e.g., Fig. 5). Joseph et al. further teaches 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, last paragraph).
In this case, the claims of the reference patent is silent regarding the limitation of “inducing immune tolerance”. However, the claimed limitation would naturally flow from the teachings of the reference patent, since the same effective amount of the same compound (methotrexate) is being administered to the same subject in need of treatment with the same therapeutic (human acid alpha-glucosidase) in a single cycle. In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances; therefore, by practicing the method taught by the reference patent, one will also be " inducing immune tolerance” in the subject. Please note the human acid alpha-glucosidase taught by the reference patent is a protein therapeutic and an enzyme.
Regarding the limitation of “wherein the subject is a human” in claim 11, and the limitation of “wherein the subject in a Pompe disease patient” in claim 54, 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 reference patent to administer incorporate a human with Pompe disease as the subject. One would have been motivated to do so, because Joseph et al. teaches recombinant human acid [Symbol font/0x61]-glucosidase is an enzyme replacement therapies (ERT) for a human disease called infantile-onset Pompe disease; and methotrexate can reduce recombinant human acid [Symbol font/0x61]-glucosidase-specific antibody response. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that administering the therapeutic (human acid alpha-glucosidase) and methotrexate to a human in need of the treatment of human acid alpha-glucosidase, including a human with Pompe disease, would successfully increase the percentage of B regulatory cells and induce immune tolerance by reducing recombinant human acid [Symbol font/0x61]-glucosidase-specific antibody response.
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 method treatment in a single cycle of 2 consecutive days would have successfully control the rhGAA-specific immune responses while increasing the percentage of B regulatory cells in the B cell population.
Therefore, the nonstatutory double patenting rejection applies.
Claims 1, 7, 11, 20, 22-25 and 54 are 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).
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 (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 a-glucosidase (see claims 13-14); wherein the methotrexate is administered at about 0.1 mg/kg to about 5 mg/kg (see claim 15). Please note the human acid [Symbol font/0x61]-glucosidase taught by the reference patent is a protein therapeutic and an enzyme.
The reference patent does not teach the subject is human as claimed in claim 11.
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 (see e.g., p. 138, right column, 1st paragraph). Joseph et al. further teaches 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), which is a mouse model of Pompe disease that recreates the genetic deficiency observed in humans disease by deleting the endogenous expression of GAA (see e.g., p. 138, right column, last paragraph to p. 139, left column, line 11).
In this case, the claims of the reference patent is silent regarding the limitation of “inducing immune tolerance”. However, the claimed limitation would naturally flow from the teachings of the reference patent, since the same effective amount of the same compound (methotrexate) is being administered to the same subject in need of treatment with the same therapeutic (human acid alpha-glucosidase) in a single cycle. In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances; therefore, by practicing the method taught by the reference patent, one will also be "inducing immune tolerance” in the subject.
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 the reference patent to incorporate human as the subject in need of treatment with human acid [Symbol font/0x61]-glucosidase. One would have been motivated to do so, because Joseph et al. teaches recombinant human acid [Symbol font/0x61]-glucosidase is an enzyme replacement therapies (ERT) for a human disease called infantile-onset Pompe disease. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that said method would have successfully treat the human in need of treatment with human acid [Symbol font/0x61]-glucosidase for Pompe disease.
Therefore, the nonstatutory double patenting rejection applies.
Conclusion
No claims are allowed.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628