Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 13 April 2016 has been entered.
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 13 April 2016.
CLAIMS UNDER EXAMINATION
Claims 1, 3-5, 7-8, 11-12, 39, 41, 43, 48-49 and 51-56 are pending and have been examined on their merits.
PRIORITY
Claim 1 recites a method of treating Pompe disease comprising administering 100 mg to 300 mg of N-butyl-deoxynojirimycin. Examiner notes none of the Provisional Applications provide support for N-butyl-deoxynojirimycin. PCT/US13/39215, filed on 02 May 2013, provides support for N-Butyl DNJ (see page 5, line 10).
REJECTIONS
Claim Rejections - 35 USC § 103
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, 3, 7-8, 11-12, 39, 41 and 49 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Do et al. (previously cited; Therapy Regimens, Dosing Regimens And Stable Medicaments For The Treatment of Pompe Disease. US 2010/0119502, 2010) in view of Rettner et al. (previously cited; The Weight of the World: Researchers Weigh Human Population 2013), Khanna et al. (previously cited; The Pharmacological Chaperone AT2220 Increases Recombinant Human Acid a-Glucosidase Uptake and Glycogen Reduction in a Mouse Model of Pompe Disease. PLOS ONE 7(7): e40776. 18 July 2012) and Parenti et al. (Pharmacological Enhancement of Mutated α-Glucosidase Activity in Fibroblasts from Patients with Pompe Disease. Molecular Therapy Vol. 15 no. 3, March 2007).
Do et al. teach a method for treating Pompe disease ([0007]). Do treats a human ([0039]). Do teaches administering an acid α-glucosidase (GAA enzyme) (e.g. a recombinant human GAA (rhGAA)) (an enzyme replacement therapy) in combination with an ASSC (active site-specific chaperone) for the GAA enzyme ([0007] [0076]).
Regarding the rhGAA:
Do teaches Myozyme is recombinant human GAA ([0018]). Do teaches 10 mg/kg ([0106] [0120]) to 40 mg/kg Myozyme ([0131]) can be administered for treatment.
Do teaches administering a dose of 10 mg/kg by infusion ([0021]).
Regarding the ASSC: Do teaches an embodiment in which the ASSC is N-butyl-deoxynojirimycin (NB-DNJ) ([0011]). Do teaches ASSC is administered in a dose between about 10 mg/kg to 1000 mg/kg to a subject ([0075]). The art teaches an ASSC (e.g., 1-DNJ) is administered at 10 mg/kg, 100 mg/kg or 1000 mg/kg, both prior to and following infusion of Myozyme ([0076]). At [0106] the art administers 10 mg/kg 1-DNJ to a mouse. As evidenced by Khanna et al., 10 mg/kg 1-DNJ-HCL in a mouse is equivalent to administering 200 mg to a human (see page 3, right column, last paragraph).
It is also noted the instant specification states “a dose of 30 mg/kg of DNJ (AT2220) and NB-DNJ (AT2221) for a mouse is equivalent to 600 mg in humans” (see page 8, line 27; see page 62, lines 19-20). Therefore, as evidenced by the Instant Specification, the dosing for DNJ and NB-DNJ is equivalent.
Regarding formulation: The art teaches intravenous infusion for the replacement enzyme, and oral administration for the ASSC ([0081]).
Regarding the order of administration: The art teaches administration of rhGAA every two weeks ([0076]). The art teaches an embodiment where the GAA is Myozyme, and is administered via infusion and the ASSC is administered prior to infusion ([0076]). Therefore the art teaches human acid α-glucosidase enzyme is administered after ASSC.
Do also teaches the following:
the term “Pompe Disease” refers to all types of Pompe Disease ([0065]). Do teaches Pompe disease affect subjects younger than 2 years old to the second or third decade of life ([0004]). A subject in the second or third decade of life is interpreted to be an adult.
The teachings of Do are as follows:
Do treats Pompe disease.
Do teaches treating a human.
Do teaches Pompe disease affects adults.
Do administers rhGAA by infusion. Do teaches rhGAA is administered every two weeks.
Do administers ASSC orally. Do teaches ASSC can be NB-DNJ or DNJ.
Do administers the human equivalent of 1-DNJ-HCL (200 mg) to a mouse.
The deficiencies of Do are:
The art does not teach the adult subject weights 55.8-109 kg.
The art does not explicitly 200 mg NB-DNJ to a human.
Rettner et al. teach the average body mass, globally, is 136 pounds (62 kilograms) (see page 2, third paragraph).
Khanna teaches studies the effect of combined therapy in animal models of Pompe disease (Abstract). The art teaches co-administration of AT2220 (1-deoxynojirimycin hydrochloride, duvoglustat hydrochloride) and rhGAA in GAA KO mice (Abstract).
Khanna administers 20 mg/kg rhGAA (see page 3, right column, last paragraph).
Khanna teaches the doses of AT2220 were limited to 10 and 30 mg/kg, which yield plasma exposures in mice that are comparable to those seen in humans following oral administration of 200 and 600 mg AT2220, respectively (see page 3, right column, last paragraph). Therefore Khanna teaches a 10 mg/kg dose of AT2220 (1-DNJ-HCL) yields plasma exposures in mice that is comparable to those seen in humans following oral administration of 200 mg.
Parenti studies the effects of the two imino sugars, DNJ and its derivative NB-DNJ on glucosidase activity in cells from patients with Pompe disease (Abstract). The art teaches patients with “late-onset” disease (Abstract). Late-onset includes adult forms (see page 508, right column, first paragraph). The art teaches a 20 year old patient that is wheelchair bound (see first paragraph of Materials and Methods; Patient 3). The patient is interpreted to be human. It is noted the art teaches patients were on ERT (enzyme replacement therapy; same cited section). The art teaches ERT is rhGAA (see page 508, right column, second paragraph).
Parenti uses the same concentration of DNJ and NB-DNJ (see page 513, left column, fifth paragraph), and disclose the imino sugars have a “similar effect” (page 512, left column, second paragraph). The art teaches both imino sugars enhance the activity of GAA (page 511, right column, second paragraph). Parenti demonstrates a significant increase of GAA activity after imino sugar treatment (Abstract).
It would have been obvious to one of ordinary skill at the time of the invention to combine the teachings of Do to treat Pompe disease in an adult human. One would have been motivated to do so since Do teaches a human in the second or third decade of life can be treated using the disclosed method. The skilled artisan would treat a human that weighs between 55.8-109 kg since the average human weighs 62 kilograms (as taught by Ratner). One would have had a reasonable expectation of success since Do teaches human adults can be treated by administering rhGAA in combination with an ASSC.
It would have been obvious to administer NB-DNJ as the ASSC in the disclosed method. See KSR E. In this case, Do identifies NB-DNJ as an ASSC that can be used to treat Pompe disease. One would had a reasonable expectation of success since Do teaches it can be used in the disclosed method and Parenti teaches DNJ and NB-DNJ have a similar effect. One of ordinary skill would have been motivated to administer NB-DNJ prior to rhGAA since Do teaches an ASSC can be administered before rhGAA.
It would have been obvious to administer 200 mg NB-DNJ to a human.
Do administers 10 mg/kg DNJ-HCL to treat a mouse and Khanna teaches this amount is comparable to administering 200 mg to treat a human. As taught by Parenti, DNJ and NB-DNJ have a similar effect when used in the same amount. As evidenced by the specification, the dosing for DNJ and NB-DNJ is equivalent. Therefore one would try using the dose taught by Khanna (200 mg) when administering NB-DNJ to a human. One would have had a reasonable expectation of success since Parenti teaches DNJ-HCL and NB-DNJ have a similar effect when used at the same amount. One would have expected similar results since each reference is directed to treating Pompe disease. Therefore claim 1 is rendered obvious as claimed.
Claim 3 recites the amount of NB-DNJ administered is 225 mg to 275 mg. Do teaches administering a dose equivalent to 200 mg in humans. Do also teaches ASSC can be administered in doses between 10-1000 mg/kg. This range would encompass a human dosage of 225 mg to 275 mg.
It would have been obvious to administer 225 mg to 275 mg to treat Pompe disease. One would have been motivated to do so since Do teaches ASSC can be administered in doses between 10-1000 mg/kg. Because Do teaches the amount of ASSC administered (mg) is based on the weight of the patient (kg) and the symptoms of the patient ([0051]), one would optimize the dose to achieve the desired therapeutic effect. See MPEP 2133.03 Therefore, the examiner asserts the claimed concentration is prima facie obvious. Therefore claim 3 is included in this rejection.
At [0076] Do teaches treating Pompe disease by administering an ASSC prior to, and in regular intervals after, α-glucosidase administration. Do teaches administration of the chaperone 2 hours (hence, about 2 hours) prior to administration of a replacement enzyme ([0076]). Therefore claim 7 is rejected.
Claim 8 recites the term “about 1 hour”. The claim does not disclose the values encompassed by the term “about. The instant specification filed on 31 October 2014 discloses the following at page 12, lines 8-15:
The terms “about” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Typical, exemplary degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Alternatively, and particularly in biological systems, the terms “about” and “approximately” can mean values that are within an order of magnitude, preferably within 5-fold and more preferably within 2-fold of a given value. Numerical quantities given herein are approximate unless stated otherwise.
While examples are provided, an explicit definition of the values encompassed by the term “about” is not stated in the specification.
Do teaches dosing the chaperone 30 minutes prior to rhGAA injection (supra). 30 minutes is broadly interpreted to read on “about” 1 hour prior to administration of the recombinant human GAA since it is within the claimed range. Further, the values are sufficiently close that one would have expected them to have the same properties since Do and the instant claims are both directed to treating the same disease. See MPEP 2144.05(I). Therefore claim 8 is rejected.
Do teaches rhGAA ([0069]). Therefore claim 11 is included in this rejection.
Claim 12 recites NB-DNJ is administered “as an adjuvant”. The claims do not
recite any chemical characteristics distinguishing the claimed NB-DNJ from that
of the prior art. Because Do teaches administration of NB-DNJ as an ASSC and rhGAA, NB-DNJ is interpreted to be an adjuvant to rhGAA. Therefore claim 12 is rejected.
Claim 39 recites the amount of NB-DNJ administered is 237.5 mg to 262.5 mg. The teachings of Do as set forth above are reiterated.
It would have been obvious to administer 237.5 mg to 262.5 mg to treat Pompe disease. One would have been motivated to do so since Do teaches ASSC can be administered in doses between 10-1000 mg/kg. Because Do teaches the amount of NB-DNJ administered (mg) based on the weight of the patient (kg) and the symptoms of the patient ([0051]), one would optimize the dose based on the weight of the patient and symptoms of the disease being treated. See MPEP 2133.03. Therefore, the examiner asserts the claimed concentration is prima facie obvious. Therefore
Claim 39 is included in this rejection.
Claim 41 recites the amount of NB-DNJ administered is 100 mg to 200 mg. Administering 200 mg is rendered obvious on the same grounds recited in the rejection of claim 1. Claim 41 is included in this rejection.
Claim 49 recites administering the NB-DNJ and rhGAA replacement therapy to the subject every two weeks without other administration of NB-DNJ and rhAA. This is interpreted to mean each compound is only administered once in a two week period. Because the claim recited “every”, the administration can be repeated after two weeks.
In Example 9, Do teaches a subject is administered a single dose of Myozyme (40 mg/kg) every other week for 8 weeks. Every other week is interpreted to read on every 2 weeks. In addition, mice received ASSC 30 minutes prior to Myozyme administration.
Khanna teaches KO mice are administered AT2220 (10 or 30 mg/kg) once every other week for 8 weeks (see last paragraph of page 3 bridging first paragraph of page 5). Thirty minutes after AT2220, rhGAA (20 mg/kg) was administered (same cited section).
It would have been obvious to combine teachings of the prior art by administering the claimed ASSC and enzyme replacement once every 2 weeks. One would have been motivated to do so since Do teaches administering ASSC and enzyme replacement every other week and Khanna teaches 10 mg/kg ASSC (equivalent to 200 mg in human) and enzyme replacement can be administered every other week for 8 weeks. One would have had a reasonable expectation of success since Khanna teaches this regimen can be used to treat Pompe disease. One would have expected similar results since Do and Khanna are both directed to treating Pompe disease. Therefore claim 49 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
RESPONSE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 13 April 2026 are acknowledged.
Argument 1: The arguments state Figure 24 shows when a dose of NB-DNJ is administered orally to a subject followed by intravenous rhGAA, the bioavailability of GAA over time is higher than DNJ and rhGAA. The Applicant argues the prior art does not teach this effect.
Response to Argument 1:Do teaches NB-DNJ as an ASCC (supra). Do teaches rhGAA (supra). Do teaches administration with ASCC increases the in vitro and in vivo stability of GAA (Abstract).
Figure 24 is directed to a method of treating mice. It is not directed to an adult human. A dose of 100 mg/kg (DNJ or NB-DNJ) is administered 30 minutes prior to rhGAA at 10 mg/kg. The experiment in Figure 24 is not commensurate with the scope of claim 1.The specification states “As shown in FIG. 24, AT2220 and AT2221 increased the circulating half-life of rhGAA by at least ˜2-fold. N-butyl-DNJ (AT2221) and 1-DNJ (AT2220) have a similar effect on pharamacokinetics of rhGAA” ([0215]). Therefore the passage cited by the Applicant states the same dose of DNJ and NB-DNJ results in a similar effect on the pharamacokinetics of rhGAA.
Argument 2: The Applicant argues the similar effect taught by Parenti would not have been expected in vivo. The Applicant argues the claims are directed to enzyme replacement, while Parenti teaches mutated GAA.
Response to Argument 2: Parenti teaches DNJ and NB-DNJ have a similar effect when used at the same concentration on cells from patients with Pompe disease. As evidenced by the Instant Specification, the dosing for DNJ and NB-DNJ is equivalent (supra). The Applicant has not presented evidence the in vitro and in vivo effects are different. Parenti is not relied upon to teach administration of rhGAA and ASSC. Do teaches this limitation. It is also noted the art teaches patients receive enzyme replacement therapy. The arguments are not persuasive.
Claims 4-5, 43, 48, 51-56 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Do in view of Rettner, Khanna and Parenti as applied to claim 1 above, and further in view of Lockhart et al. (previously cited; Dosing Regimens For The Treatment of Lysosomal Storage Diseases Using Pharmacological Chaperones. US 2010/0266571; 21 October 2010).
Claim 1 is rejected as recited supra. The teachings of the prior art as set forth above are reiterated.
Do does not explicitly teach fasting for about 0.5 to about 4 hours before and after administration of the ASSC (claim 4).
Do does not explicitly teach fasting for at least about 2 hours before and after administration of the ASSC (claim 5).
Lockhart teaches a method of treating lysosomal disorders (Abstract). The art teaches that Pompe disease is a lysosomal disorder ([0006]). Lockhart teaches DNJ chaperones can be used to treat Pompe disease (See [0196]). When treating lysosomal disorders, the art teaches fasting for about 2 hours prior to, and two hours following administration of drug chaperones (See [0066] [0164]). The art teaches that doing so prevents “food effect” ([0249])
It would have been obvious to combine the teachings of Do and Lockhart by fasting for about 2 hours prior to and following administering the ASSC chaperone taught by Do since Lockhart teaches one should fast before and after administering chaperones when treating Pompe disease. Lockhart teaches doing so is advantageous to avoid the effect of food on drug pharmacokinetics, hence providing motivation for fasting. One would expect similar results since Do and Lockhart both use chaperones to treat Pompe disease. This time reads on the limitations of claims 4-5. Therefore claims 4-5 are rendered obvious.
Regarding independent claim 43: the claim recites orally administering a single dose of 225 mg to 275 mg NB-DNJ and administering a single dose of about 20 mg/kg rh-GAA “after each administration of” NB-DNJ. Claim 43 recites the term “about”. As set forth above, the instant specification does not provide an explicit definition for “about”.
The teachings of the prior art are reiterated.
Do treats Pompe disease.
Do teaches treating a human.
Do teaches Pompe disease affects adults.
Do administers rhGAA by infusion.
Do teaches 10-40 mg/kg rhGAA (Myozyme) can be administered supra. Do teaches rhGAA infusion.
Do administers ASSC orally. Do teaches ASSC can be NB-DNJ or DNJ.
Do administers the human equivalent of 1-DNJ-HCL (200 mg) to a mouse.
It would have been obvious to one of ordinary skill at the time of the invention to combine the teachings of Do to treat Pompe disease in an adult human. One would have been motivated to do so since Do teaches a human in the second or third decade of life can be treated using the disclosed method. The skilled artisan would treat a human that weighs between 55.8-109 kg since the average human weighs 62 kilograms (as taught by Ratner). One would have had a reasonable expectation of success since Do teaches human adults can be treated by administering rhGAA in combination with an ASSC.
It would have been obvious to administer NB-DNJ as the ASSC in the disclosed method. See KSR E. Do identifies NB-DNJ as an ASSC that can be used to treat Pompe disease. One would had a reasonable expectation of success since Do teaches it can be used in the disclosed method and Parenti teaches DNJ and NB-DNJ have a similar effect. One of ordinary skill would have been motivated to administer NB-DNJ prior to rhGAA since Do teaches an ASSC can be administered before rhGAA.
Do teaches dosing the chaperone 30 minutes prior to rhGAA injection (supra). 30 minutes is broadly interpreted to read on “about” 1 hour prior to administration of the recombinant human GAA since it is within the claimed range. The values are sufficiently close that one would have expected them to have the same properties since Do and the instant claims are both directed to treating the same disease.
It would have been obvious to administer 225 mg to 275 mg of NB-DNJ to a human.
One would have been motivated to do so since Do teaches administering a 10 mg/kg dose of DNJ-HCL to a mouse to treat Pompe disease and Khanna teaches this amount is comparable to administering 200 mg to treat a human. As taught by Parenti, DNJ and NB-DNJ have a similar effect when used in the same amount. One of ordinary skill would optimize the dosage administered to a human to achieve a therapeutically effective dose that results in a therapeutic response. The MPEP teaches it is not inventive to discover the optimum or workable ranges by routine experimentation
One would have had a reasonable expectation of success since Do teaches the ASSC can be administered at a dose of 10-1000 mg/kg. One would have expected similar results since each reference is directed to treating Pompe disease.
It would have been obvious to administer the claimed ASSC and enzyme replacement once every 2 weeks. One would have been motivated to do so since Do teaches administering ASSC and enzyme replacement every other week and Khanna teaches 10 mg/kg ASSC (equivalent to 200 mg in human) and enzyme replacement can be administered every other week for 8 weeks. One would have had a reasonable expectation of success since Khanna teaches this regimen can be used to treat Pompe disease. One would have expected similar results since Do and Khanna are both directed to treating Pompe disease
It would have been obvious to combine the teachings of Do and Lockhart by fasting for about 2 hours prior to and following administering the ASSC chaperone taught by Do since Lockhart teaches one should fast before and after administering chaperones when treating Pompe disease. Lockhart teaches doing so is advantageous to avoid the effect of food on drug pharmacokinetics, hence providing motivation for fasting. One would expect similar results since Do and Lockhart both use chaperones to treat Pompe disease. Therefore claim 43 is rendered obvious.
As evidenced by the instant specification, “alglucosidase alfa” is “Myozyme” (see page 2, line 16). Do teaches Myozyme (supra). Therefore claim 48 is included in this rejection.
Regarding independent claim 51:
Claim 51 recites the same range of NB-DNJ and recombinant enzyme replacement therapy recited in claim 1.
The teachings of the prior art are reiterated.
Do is silent regarding fasting.
The teachings of Lockhart are reiterated.
It would have been obvious to try administering 200 mg NB-DNJ to a human.
One would have been motivated to do so since Do administers teaches 10 mg/kg DNJ-HCL is an effective dose to treat a mouse and Khanna teaches this amount is comparable to administering 200 mg to treat a human. As taught by Parenti, DNJ and NB-DNJ have a similar effect when used in the same amount. Therefore one would try using the dose taught by Khanna (200 mg) when administering NB-DNJ to a human. One would have had a reasonable expectation of success since Parenti teaches DNJ-HCL and NB-DNJ have a similar effect when used at the same amount. One would have expected similar results since each reference is directed to treating Pompe disease.
It would have been obvious to administer the claimed dose of NB-DNJ and the claimed dose of rhGAA every 2 weeks, wherein the NB-DNJ is administered before the rhGAA, for the reasons set forth above. Fasting for 2 hours before and after administration of NB-DNJ is rendered obvious on the grounds set forth above. Therefore claim 51 is rendered obvious.
Fasting about 2 hours before and after administering NB-DNJ is rendered obvious on the grounds set forth above. Therefore claim 52 is included in this rejection.
Claim 53 recites the amount administered is between 225 mg to 275 mg. Claim 53 is rendered obvious on the same grounds recited in the rejection of claim 3 above.
Claim 54 recites the amount administered is between 237.5 mg to 262.5 mg. Claim 54 is rendered obvious on the same grounds recited in the rejection of claim 39 above.
Do teaches NB-DNJ is administered 30 minutes before rh-GAA. This is interpreted to read on about 1 hour for the reasons set forth above. Therefore claim 55 is included in this rejection.
As evidenced by the instant specification, “alglucosidase alfa” is “Myozyme” (see page 2, line 16). Do teaches Myozyme (supra). Therefore claim 56 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 270-8439.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
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