DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Amendments
Claim 78 now requires GCB and IFG to be in a molar ratio of at least about 1:2.5. Additionally, the claim now requires that the subcutaneous administration of the composition provides a level of GCB tissue exposure that is substantially the same as a level of GCB tissue exposure provided by a control GCB composition administered intravenously, when the composition and the control GCB composition are administered to the patient at a dose of 10 mg/kg of GCB.
Claim 81 no longer recites an “optional” limitation.
Claims 87-89 and 91 have been canceled.
Claim 92 now depends from claim 78.
Claim 95 has had a minor typographic change.
Claims 98-100 are newly added and limit the defect in GCase activity (claim 98), the amount of composition (claim 99) and the dose of the composition (claim 100).
Claim Objections
Previous objections to the claims
Claim 95 was objected to for a minor informality. Applicant has made the appropriate response and the objection is therefore withdrawn.
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Previous rejection under 35 U.S.C. § 103
RE: Applicant’s Response to the Rejections of Record
The pending claims were rejected over various combinations of Daniel, Do, and Schapira. Applicant traverses.
First, applicant argues that the Office has not sufficiently explained why a person having ordinary skill in the art would choose to select and modify the particular ingredients and amounts from the cited art to arrive at the claimed composition that is suitable for subcutaneous administration. Applicant argues that the position that a person having ordinary skill in the are would not have been discouraged from investigation into (or use of) subcutaneous administration is impermissible.
Specifically, applicant argues that the amended claims contain a “stability limitation” in which the administration provides a degree of GCB tissue exposure that is “substantially the same as a level of GCB tissue exposure provided by a control composition administered intravenously” (Remarks, p. 6, par. 3) and the Office has allegedly not provided sufficient explanation as to why the skilled person would have been led to arrive at the molar ratio recited in the claims to obtain the claimed degree of GCB tissue exposure.
Applicant asserts that they have demonstrated an unexpected result in the working examples. Specifically, applicant argues that the specification discloses an experiment in which subcutaneous administration of 10 mg/kg of GCB and 5 mg/kg of IFG yielded “comparable GCB tissue exposure to that of IV administration of the same dose of GCB” (Remarks, p. 7, par. 2).
Second, applicant argues that the newly added claims 99 and 100 recite exact concentrations and dosages and the cited art does not disclose that these particular amounts could be administered subcutaneously and achieve the claimed degree of tissue distribution. Thus, these claims allegedly could not be obvious over the cited art.
Applicant’s arguments have been fully considered but are not sufficient to overcome the rejections of record.
With respect to the first argument, the Examiner disagrees with the assertion that there is insufficient explanation as to why a person of ordinary skill would select and modify the ingredients of Daniel’s disclosure. As discussed in the rejection of record, a person having ordinary skill in the art would have been motivated to experiment with various amounts and ratios of GCB and IFG in order to optimize the method of treating a GCase deficiency. Additionally, Do provides evidence that a GCG : IFG ratio of 1:3 stabilizes GCB. Moreover, the examiner disagrees that the rejection impermissibly concludes that the skilled person “would not have been ‘discouraged [from] investigation into (or use of) subcutaneous administration” (Remarks, p. 6, par. 1). As discussed in the previous office action, the rejection of record does not rely on the premise that the method is obvious merely because Daniel does not teach away from the invention. The “teaching away” (or lack thereof) portion of the argument is not part of the rejection of record and has only been raised in response to applicant’s assertion that Daniel teaches away from subcutaneous administration because its working examples involve intravenous injection (an argument first made in the Remarks filed 10/17/2024 at p. 2). Instead, the rejection is based upon the premise that Daniel explicitly teaches subcutaneous administration of compositions comprising GCB which are stabilized by IFG. The pertinent sections have been replicated below and emphasis has been added.
[0170] In some aspects, the disclosure provides the use of a glucocerebrosidase enzyme replacement therapy (e.g., velaglucerase, imiglucerase or uplyso), alone or in combination with another agent(s) described herein (e.g., isofagomine tartrate, miglustat, or Genz112638), for use in treatment.
[0171] In some aspects, the disclosure provides the use of a glucocerebrosidase enzyme replacement therapy (e.g., velaglucerase or imiglucerase ), alone or in combination with another agent(s) described herein (e.g., isofagomine tartrate, miglustat, or Genz112638), for the preparation of a medicament, e.g., for treating Gaucher disease.
[0326] Isofagomine tartrate. Isofagomine tartrate (AT-2101, HGT-34100, PLICERA®) ((3R,4R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)piperidine L-(+)-tartrate; CAS No. 957230-65-8) selectively binds to and stabilizes glucocerebrosidase and facilitates proper trafficking of the enzyme to the lysosomes, the compartments in the cell where it is needed to break down glucocerebroside. See also U.S. Pat. No. 7,501,439.
[0350] The glucocerebrosidase enzyme replacement therapy described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously”.
For at least these reasons, Daniel provides sufficient motivation to arrive at a method of treating a disorder related to a dysfunction in a GCase pathway by subcutaneous administration of glucocerebrosidase and isofagomine. The next pertinent question is whether applicant has demonstrated unexpected or remarkable results.
Applicant’s argument of unexpected results is directed to the findings of Example 12, in which Group 1 was treated IV with 10 mg/kg GCB and Group 2 was treated SC with 10 mg/kg GCB and 5 mg/kg IFG.
Improved tissue exposure is inherent to subcutaneous administration of the composition taught by Daniel. As discussed above, Daniel teaches subcutaneous enzyme replacement therapy and teaches that GCase enzymes can be stabilized and properly trafficked by IFG. There is no requirement that Daniel compared the tissue exposure resulting from GCB/IFG administration through each route. "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." (MPEP § 2112). Taken as a whole, it would have been expected that co-administration of GCB and IFG leads to an improved tissue exposure because it was known (such as in Daniel and Do) that IFG stabilizes and traffics GCB.
In the interest of compact prosecution, it is noted that even if applicant has demonstrated an unexpected result, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." (MPEP § 716.02(d)). Assuming, arguendo, that the dosing and ratio are what elicit a surprising improvement in tissue exposure, the evidence of the allegedly unexpected result is widely different from the claimed invention.
As discussed above, applicant’s argument of unexpected results is directed to the findings of Example 12, in which Group 1 was treated IV with 10 mg/kg GCB and Group 2 was treated SC with 10 mg/kg GCB and 5 mg/kg IFG. The language of the amended claim 78 does not necessarily require administration of a particular amount of 10 mg/kg. Rather, the language merely recites a characteristic of the GCB/IFG composition “when the composition and the control GCB composition are administered to the patient at a dose of 10 mg/kg of GCB”. In other words, the claim merely recites how the composition may behave at a certain dosage but does not necessarily require a dosage of 10 mg/kg of GCB. Additionally, the claim allows for “a molar ratio of at least about 1:2.5.”, while the evidence involves administration of a ratio of 1:100 (40x more IFG)(see Table 13). Accordingly, if applicant’s argument for unexpected results is to be accepted, then the evidence is clearly not commensurate with the scope of the claims because the claims allow for much lower ratios of GCB to IFG (and any amount of GCB) and there would need to be evidence that the unexpected result is also seen at lower ratios and other amounts.
With respect to applicant’s second argument, although Daniel does not directly teach specific doses and molar ratios for subcutaneous administration, Daniel teaches that IFG selectively binds to and stabilizes GCB and facilitates proper trafficking of the enzyme to lysosomes ([0326). Thus, a person having ordinary skill in the art would have been prompted to perform routine experimentation to determine the optimal dosage of GCB and relative molar concentrations of IFG to GCB in order to allow IFG to bind and stabilize GCB when administered subcutaneously. A person having ordinary skill in the art could have pursued this routine experimentation to arrive at the claimed composition with a reasonable expectation success because any combination of IFG with GCB would have been expected to result in a more stable and properly trafficked therapeutic composition. And for the reasons discussed in the remarks above, there is no indication that amount of GCB or molar ratio range of IFG to GCB causes an unexpected result or imparts an unexpected characteristic on the composition. Moreover, even if the working examples demonstrated unexpected or remarkable results, claim 100 is directed to administration of a dose of 100 mg/kg GCB, which is an order of magnitude higher than the working example and the working example cannot provide probative value for unexpected results in this case.
For at least these reasons, the amended claims are considered to be obvious over the same combinations of references. In order to address applicant’s amendments to the claims, the rejections are withdrawn and new grounds of rejection are made below.
New grounds of rejection under 35 U.S.C. § 103
Claims 78-81, 83-84, 90, and 92-100 are rejected under 35 U.S.C. 103 as being unpatentable over Daniel et al. (US 2011/0027254 A1; cited in IDS filed on 08/09/2023) in view of Do (US 2011/0143419 A1; cited in IDS filed on 08/09/2023).
Daniel et al. (hereinafter Daniel) teaches enzyme replacement therapies with glucocerebrosidase (GCB) based upon the discovery that a specific GCB, velaglucerase (recombinantly produced human β-glucocerebrosidase; [0300]), elicits less of an immune response than imiglucerase upon administration to subjects ([0004]-[0005]). Specifically, Daniel teaches methods of treating subjects with Gaucher disease comprising a GCB by intravenous infusion ([0006]-[0008]).
Regarding claims 78 and 83-84, Daniel teaches methods of treating a subject (i.e., a patient in need thereof) having Gaucher disease (i.e., a disorder related to a dysfunction in a GCase pathway; see claim 84) comprising administering a glucocerebrosidase enzyme ([0006]-[0007]). In addition, Daniel teaches that the GCB can be administered alone or in combination with other agents such as isofagomine (IFG)([0170]-[0171]). Daniel teaches that the composition may be injected (i.e., administered) subcutaneously ([0350]).
Accordingly, Daniel teaches a method of treating a disorder related to a dysfunction in a GCase pathway comprising administering a composition comprising a glucocerebrosidase (GCB) and an isofagomine (IFG) to a patient in need thereof, wherein the composition is administered subcutaneously.
With respect to the new requirement that the composition is administered to the subject in a molar ratio of at least about 1:2.5, applicant defines “about” to mean up to ± 10% of the value qualified by this term (Specification, [0029]).
Although Daniel does not directly teach this limitation, Daniel teaches that IFG selectively binds to and stabilizes GCB and facilitates proper trafficking of the enzyme to lysosomes ([0326). Thus, a person having ordinary skill in the art would have been prompted to perform routine experimentation to determine the optimal relative molar concentrations of IFG to GCB in order to allow IFG to bind and stabilize GCB when administered subcutaneously. A person having ordinary skill in the art could have pursued this routine experimentation to arrive at the claimed composition with a reasonable expectation success because any combination of IFG with GCB would have been expected to result in a more stable and properly trafficked therapeutic composition. There is no indication that the claimed molar ratio range of IFG to GCB causes an unexpected result or imparts an unexpected characteristic on the composition.
Alternatively, Do teaches methods of improving recombinant protein production through the use of chaperones ([0006]). Specifically, Do provides embodiments wherein GCB is stabilized by IFG ([0015]). Do demonstrates that IFG ameliorates the loss of GCB activity ([0026]; Figure 10) and does so at multiple molar ratios including 0.5 µM : 3.0 µM (1:1.15), 0.5 µM : 30 µM (1:15), and 0.5 µM : 100 µM (1:50)([0026]). Therefore, Do provides specific molar ratios which are at least about a 3-fold molar excess to the GCB.
Accordingly, it would have been obvious to have modified the method of Daniel such that the GCB and IFG are in one of the molar ratios disclosed by Do and these ratios overlap with the claimed ratio range. There would have been a reasonable expectation of success because Do provides evidence that these ratios are ratios which effectively stabilize GCB (an effect also taught by Daniel). This obviousness is based upon the “Some Teachings, Suggestion, or Motivation in the Prior Art That Would Have Led One of Ordinary Skill To Modify the Prior Art Reference or To Combine Prior Art Reference Teachings To Arrive at the Claimed Invention” rationale set forth in in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007). See MPEP 2143(I)(G).
With respect to the new requirement that the subcutaneous administration of the composition provides a level of GCB tissue exposure that is substantially the same as a level of GCB tissue exposure provided by a control GCB composition administered intravenously, when the composition and the control GCB composition are administered to the patient at a dose of 10 mg/kg of GCB, this is considered to be an unappreciated property inherent to the administration of compositions comprising GCB and IFG. As discussed above, Daniel and Do teach that IFG stabilizes GCB and Daniel teaches administration of compositions comprising GCB and IFG. There is no requirement that Daniel tested the tissue exposure (MPEP § 716.02(d)) and applicant’s observations of the tissue exposure do not rise to a level of non-obviousness because 1) it would have been expected that the tissue exposure of GCB resulting from subcutaneous administration is improved by administration of a composition comprising GCB and IFG and 2) this property is inherent to Daniel’s methods because Daniel teaches administration of the same composition through the same route.
Thus, claims 78 and 83-84 are obvious over Daniel as a result of routine experimentation or, alternatively, over Daniel in view of Do.
Regarding claim 79, as discussed above, Daniel teaches subcutaneous injection ([0350]).
Regarding claim 80, Daniel teaches that the composition may be administered every week (i.e., once weekly) or every other week (i.e., once every other week)([0009]).
Regarding claim 81, Daniel teaches that Gaucher disease is characterized by a deficiency in glucocerebrosidase (i.e., a defect in GCase activity)([0002]).
Regarding claim 90, Daniel teaches that IFG selectively binds to and stabilizes GCB and facilitates proper trafficking of the enzyme to lysosomes ([0326). Daniel further teaches that glucocerebroside (i.e., the target of GCB) is in the spleen and liver (among other locations)([0337]). Accordingly, Daniel teaches that the exposure, activity, and bioavailability (as a result of the improved stability and trafficking) in the spleen and liver is increased.
Regarding claim 92, Daniel teaches that the composition can include sodium citrate dihydrate and polysorbate-20 ([0358]). Daniel provides a specific example which includes the use of 12.9 mg/mL sodium citrate ([0860]). The molecular weight of sodium citrate dihydrate is 294.10 g/mol. Accordingly, Daniel teaches the use of 43.9 mM sodium citrate dihydrate. In the same example, Daniel teaches the use of 0.11 mg/mL polysorbate-20, which is equivalent to 0.011% w/v. Although 43.9 mM sodium citrate and 0.011% w/v polysorbate-20 are not amounts encompassed by any of the elements of this claim, 43.9 mM is close to 50 mM and 0.011% polysorbate-20 is close to 0.01%. Thus, Daniel’s teachings are close to the amounts claimed in element “a)” of this claim. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close (MPEP § 2144.05(I)). In addition, there is no evidence that changing the molar amount of sodium citrate from 43.9 mM to 50 mM or changing the percent of polysorbate-20 from 0.011% to 0.01% is critical to the invention (MPEP § 2144.05(III)(A)).
Alternatively, although Daniel does not teach the specific amounts recited in the claim, a person having ordinary skill in the art would have been expected to routinely experiment with the amount of sodium citrate and would have been expected to have used at least one of the claimed formulations with a reasonable expectation of success. Daniel teaches that the polysorbate stabilizes and composition and the sodium citrate is a buffer salt. Accordingly, the result of the routine experimentation would have been a more stable and buffered composition. There is no indication that the claimed formulations result in an unexpected result.
Regarding claim 93, Daniel’s administered GCB is velaglucerase ([0026] and [0030]), which is also referred to as velaglucerase alfa ([0304]).
Regarding claim 94, Daniel teaches reconstitution of the velaglucerase with water ([0011], [0033], and [0309]). Thus, there is a reasonable expectation that the pH of Daniel’s composition is “about 7.0”.
Regarding claim 95, as discussed above, Daniel does not teach a specific molar ratio but nonetheless makes obvious the claimed range of about 1:10 to about 1:30 or about 1:3.00 through routine experimentation. Alternatively, Do makes obvious the molar ratios of at least 1:1.15. For these same reasons, it would have been obvious to have arrived at any of the claimed molar ratios and there is no indication that the claimed molar ratio range causes an unexpected result or imparts an unexpected characteristic on the composition.
Regarding claim 96, Daniel does not teach a specific temperature for the composition.
Nevertheless, a person having ordinary skill in the art would have been expected to routinely experiment with different temperatures in order to optimize enzymatic efficacy. There would have been a reasonable expectation of success because the claim currently encompasses any temperature.
Alternatively, Do teaches stabilization of the “proper conformation” to increase shelf-life, activity, or in vivo efficacy ([0041]). Do teaches that the stabilization can be observed by greater resistance to unfolding due to temperature increases (Id.). Do demonstrates that when combined with IFG, GCB is properly folded at temperatures of about 40°C (Fig. 8). Accordingly, it would have been obvious to have administered the composition at a temperature of 40°C (a value falling in the range of at least 20°C).
Regarding claim 97, Daniel teaches that the composition typically includes GCB and a pharmaceutically acceptable carrier ([0354]) and the carrier includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents ([0355]). Daniel gives examples of components included in the composition such as sterile water, sucrose, and polysorbate ([0358]). Accordingly, Daniel teaches that the composition may comprise pharmaceutically acceptable excipients. In addition, Daniel teaches that the composition may comprise a buffer salt such as citrate ([0172]). This is a pharmaceutically acceptable salt because applicant defines pharmaceutically acceptable salts as including citric acid (Specification, [0084]).
Regarding claim 98, as discussed above, Daniel teaches that Gaucher disease is characterized by a deficiency in glucocerebrosidase ([0002]). This is considered to be a decreased enzymatic activity.
Regarding claims 99-100, as discussed above, although Daniel does not directly teach dosing amounts and concentrations, Daniel teaches that IFG selectively binds to and stabilizes GCB and facilitates proper trafficking of the enzyme to lysosomes ([0326). Thus, a person having ordinary skill in the art would have been prompted to perform routine experimentation to determine the optimal dosage of GCB and IFG in order to allow IFG to bind and stabilize GCB when administered subcutaneously and to arrive at a method which effectively treats a disorder related to a dysfunction in a GCase pathway. A person having ordinary skill in the art could have pursued this routine experimentation to arrive at the claimed composition with a reasonable expectation success because any combination of IFG with GCB would have been expected to result in a more stable and properly trafficked therapeutic composition and because the broad definition of “treating” allows for any positive effect on the disorder. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical (MPEP § 2144.05(II)(A)). There is no indication that the claimed concentrations and dosing amounts elicit an unexpected result or impart an unexpected characteristic on the composition .
Claims 78-84, 90, and 92-100 are rejected under 35 U.S.C. 103 as being unpatentable over Daniel et al. (US 2011/0027254 A1; cited in IDS filed on 08/09/2023) in view of Do (US 2011/0143419 A1; cited in IDS filed on 08/09/2023), as evidenced by Schapira (Molecular and Cellular Neuroscience, 2015, Vol. 66, pages 37-42).
The teachings of Daniel and Do are set forth above and applied herein. Daniel and Do are found to render obvious claims 78-81, 83-84, 90, and 92-100.
Regarding claim 82, as discussed above, Daniel in view of Do makes obvious the method of claim 78. However, neither Daniel nor Do teaches that the disorder related to a dysfunction in a GCase pathway comprises alpha-synuclein dysregulation.
Nevertheless, Schapira reviews the etiology of Parkinson disease (PD) and provides evidence that Gaucher disease is a disorder comprising alpha-synuclein dysregulation. Specifically, Schapira teaches that GCase metabolizes glucocerebroside to glucose and ceramide, wherein mutations of the GCase GBA1 gene cause Gaucher disease (p. 38, left col., par. 3). Schapira further teaches that the relationship between GCase and alpha-synuclein is reciprocal (i.e., downregulation of GCase leads to increase of alpha-synuclein)(p. 39, Fig. 1). Accordingly, because Daniel teaches treatment of Gaucher disease (which is related to a downregulation of GCase) and GCase dysfunction is associated with increased (i.e., dysregulated) alpha-synuclein, Gaucher disease is a disorder comprising alpha-synuclein dysregulation.
Thus, claim 82 is obvious over Daniel in view of Do, as evidenced by Schapira.
Claims 78-81, 83-86, 90, and 92-100 are rejected under 35 U.S.C. 103 as being unpatentable over Daniel et al. (US 2011/0027254 A1; cited in IDS filed on 08/09/2023) in view of Do (US 2011/0143419 A1; cited in IDS filed on 08/09/2023) and Schapira (Molecular and Cellular Neuroscience, 2015, Vol. 66, pages 37-42).
The teachings of Daniel and Do are set forth above and applied herein. Daniel and Do are found to render obvious claims 78-81, 83-84, 90, and 92-100.
Regarding claims 85-86, neither Daniel nor Do teaches that the method can be used for treating neurodegenerative disorders such as Parkinson disease, Alzheimer’s disease, and Lewy body dementia.
Nevertheless, as discussed above, Schapira reviews the etiology of Parkinson disease (PD). Schapira teaches that GCase metabolizes glucocerebroside to glucose and ceramide and mutations of the GCase GBA1 gene cause Gaucher disease (p. 38, left col., par. 3). Schapira further teaches that the relationship between GCase and alpha-synuclein is reciprocal (i.e., downregulation of GCase leads to increase of alpha-synuclein)(p. 39, Fig. 1). Schapira teaches that “it is clear that the presence of a GBA mutation in homozygous or heterozygous form is associated with an approximately 20-fild increase in the risk for PD” (abstract) and that there are several candidate pathways through which GCase deficiency may promote pathogenesis of PD, including reciprocal alpha-synuclein levels, lysosomal dysfunction, ERAD, calcium dysregulation, and mitochondrial abnormalities (p. 40, right col., par. 2). Schapira further teaches that “improving the trafficking of mutant GCase by chaperones may enhance GCase not only by lysosomal localization but also by upregulation and reducing the interaction of GCase with alpha-synuclein will increase turnover of alpha-synuclein and reduce its propensity to aggregate (p. 40, right col., par. 4). Schapira concludes that targeting the GCase-lysosomal pathway is an opportunity for development of neuroprotective drugs in PD (p. 40, right col., par. 5).
Since Daniel teaches enzyme therapy for the treatment of Gaucher disease and Schapira teaches that GCase dysfunction associated is intimately linked with the pathogenesis of Parkinson disease, it would have been obvious to have modified the method made obvious by Daniel and Do such that it is directed to treatment of Parkinson disease. There would have been a reasonable expectation of success because Schapira teaches multiple ways in which improving GCase function reduces alpha-synuclein interactions and suggests that targeting this pathway is a potential for development of neuroprotective drugs. This obviousness is based upon the “Some Teachings, Suggestion, or Motivation in the Prior Art That Would Have Led One of Ordinary Skill To Modify the Prior Art Reference or To Combine Prior Art Reference Teachings To Arrive at the Claimed Invention” rationale set forth in in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007). See MPEP 2143(I)(G).
Thus, claims 85-86 are obvious over Daniel in view of Do and Schapira.
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.
Previous Double Patenting Rejections
Applicant traverses the double patenting rejections of record by arguing that the cited references, alone or in combination, fail to teach or suggest a method of treating a disorder related to a dysfunction in a GCase pathway comprising administering a composition comprising the specified amounts of GCB and IFG, by way of subcutaneous administration and with the claimed degree of tissue distribution.
As discussed above, the claims are obvious over the combination of Daniel, Do, and Shapira. For the reasons discussed in the rejections of record, the claims are obvious over the cited patents in view of Daniel, Do, and Shapira. Similarly, the amended claims are obvious over the same patents in view of Daniel, Do, and Shapira. Accordingly, the rejections have been withdrawn and new grounds of rejection are made below.
New grounds of rejection for double patenting
Claims 78-86, 90, and 92-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 11,571,466 B2 in view of Daniel et al. (US 2011/0027254 A1; cited in IDS filed on 08/09/2023), Do (US 2011/0143419 A1; cited in IDS filed on 08/09/2023), and Schapira (Molecular and Cellular Neuroscience, 2015, Vol. 66, pages 37-42).
Claims 1-5 of ‘466 are directed to pharmaceutical compositions comprising velaglucerase (claims 1-4) and a method of treating Gaucher disease by administering the composition of claim 1.
Regarding claims 78 and 85-86, claim 5 of ‘466 teaches a method of treating Gaucher disease (i.e., a disorder related to a dysfunction in a GCase pathway) comprising administering a composition comprising velaglucerase (i.e., a glucocerebrosidase) in a subject (i.e., a patient in need thereof).
‘466 differs from the instant claim because it does not teach the coadministration of an isofagomine (or the recited molar ratio) and does not teach subcutaneous administration.
Nevertheless, Daniel teaches a composition comprising GCB and IFG and teaches that the composition may be injected subcutaneously ([0350]). Accordingly, it would have been obvious to have administered the composition subcutaneously.
And although neither ‘466 nor Daniel directly teach administration in the recited ratios, Daniel teaches that IFG selectively binds to and stabilizes GCB and facilitates proper trafficking of the enzyme to lysosomes ([0326). Thus, a person having ordinary skill in the art would have been prompted to perform routine experimentation to determine the dosage of GCB and relative molar concentrations of IFG to GCB in order to allow IFG to bind and stabilize GCB when administered subcutaneously. A person having ordinary skill in the art could have pursued this routine experimentation to arrive at the claimed composition with a reasonable expectation success because any combination of IFG with GCB would have been expected to result in a more stable and properly trafficked therapeutic composition. There is no indication that the claimed amount of GCB or molar ratio range of IFG to GCB causes an unexpected result or imparts an unexpected characteristic on the composition.
Alternatively, Do teaches methods of improving recombinant protein production through the use of chaperones ([0006]). Specifically, Do provides embodiments wherein GCB is stabilized by IFG ([0015]). Do demonstrates that IFG ameliorates the loss of GCB activity ([0026]; Figure 10) and does so at multiple molar ratios including 0.5 µM : 3.0 µM (1:1.15), 0.5 µM : 30 µM (1:15), and 0.5 µM : 100 µM (1:50)([0026]). Therefore, Do provides specific molar ratios which are at least about a 3-fold molar excess to the GCB.
Accordingly, it would have been obvious to have modified the method of ‘466 in view of Daniel and Do such that the GCB and IFG are in one of the molar ratios disclosed by Do and these ratios overlap with the claimed ratio range.
And although claim 78 now requires a tissue distribution limitation, this limitation is merely descriptive of an inherent property associated with administration of GCB and IFG subcutaneously.
Thus, claim 78 is obvious over ‘466 in view of Daniel, Do, and Shapira.
Regarding claim 79, as discussed above, claim 5 of ‘466 merely teaches administration but does not teach a specific route. Daniel teaches that the composition may be injected subcutaneously ([0350]).
Regarding claim 80, the claims of ‘466 do not specify a particular dosing regimen.
Nevertheless, Daniel teaches that the composition may be administered every week (i.e., once weekly) or every other week (i.e., once every other week)([0009]). Accordingly, it would have been obvious to have administered the composition once a week or once every other week.
Regarding claims 81 and 98, the claims of ‘466 do not teach that the disorder is a defect in GCase activity. Daniel teaches that Gaucher disease is characterized by a deficiency in glucocerebrosidase (i.e., a decreased enzymatic activity)([0002]). Accordingly, Gaucher disease (taught by claim 5 of ‘466) is a disorder comprising a defect in GCase activity.
Regarding claim 82, claim 5 of ‘466 is directed to treatment of Gaucher disease but does not teach that it is an alpha-synuclein dysregulation.
Schapira reviews the etiology of Parkinson disease (PD) and provides evidence that Gaucher disease is a disorder comprising alpha-synuclein dysregulation. Specifically, Schapira teaches that GCase metabolizes glucocerebroside to glucose and ceramide and mutations of the GCase GBA1 gene cause Gaucher disease (p. 38, left col., par. 3). Schapira further teaches that the relationship between GCase and alpha-synuclein is reciprocal (i.e., downregulation of GCase leads to increase of alpha-synuclein)(p. 39, Fig. 1). Accordingly, because ‘466 teaches treatment of Gaucher disease (which is related to a downregulation of GCase) and GCase dysfunction is associated with increased (i.e., dysregulated) alpha-synuclein, Gaucher disease is a disorder comprising alpha-synuclein dysregulation.
Regarding claims 85-86, neither ‘466, Daniel nor Do teaches that the method of ‘466 can be used for treating neurodegenerative disorders such as Parkinson disease, Alzheimer’s disease, and Lewy body dementia.
Nevertheless, as discussed above, Schapira reviews the etiology of Parkinson disease (PD). Schapira teaches that GCase metabolizes glucocerebroside to glucose and ceramide and mutations of the GCase GBA1 gene cause Gaucher disease (p. 38, left col., par. 3). Schapira further teaches that the relationship between GCase and alpha-synuclein is reciprocal (i.e., downregulation of GCase leads to increase of alpha-synuclein)(p. 39, Fig. 1). Schapira teaches that “it is clear that the presence of a GBA mutation in homozygous or heterozygous form is associated with an approximately 20-fild increase in the risk for PD” (abstract) and that there are several candidate pathways through which GCase deficiency may promote pathogenesis of PD, including reciprocal alpha-synuclein levels, lysosomal dysfunction, ERAD, calcium dysregulation, and mitochondrial abnormalities (p. 40, right col., par. 2). Schapira further teaches that “improving the trafficking of mutant GCase by chaperones may enhance GCase not only by lysosomal localization but also by upregulation and reducing the interaction of GCase with alpha-synuclein will increase turnover of alpha-synuclein and reduce its propensity to aggregate (p. 40, right col., par. 4). Schapira concludes that targeting the GCase-lysosomal pathway is an opportunity for development of neuroprotective drugs in PD (p. 40, right col., par. 5).
Accordingly, because ‘466 teaches enzyme therapy for the treatment of Gaucher disease and Schapira teaches that GCase dysfunction associated is intimately linked with the pathogenesis of Parkinson disease, it would have been obvious to have modified the method of claim 5 of ‘466 such that it is directed to treatment of Parkinson disease.
Regarding claim 90, the claims of ‘466 do not teach the specific effect recited in this claim. Nevertheless, Daniel teaches that IFG selectively binds to and stabilizes GCB and facilitates proper trafficking of the enzyme to lysosomes ([0326). Daniel further teaches that glucocerebroside (i.e., the target of GCB) is in the spleen and liver (among other locations)([0337]). Accordingly, Daniel teaches that the exposure, activity, and bioavailability (as a result of the improved stability and trafficking) in the spleen and liver is increased.
Regarding claim 92, claim 1 of ‘466 recites about 12.9 mg/mL sodium citrate dihydrate and about 0.11 mg/mL polysorbate-20. The molecular weight of sodium citrate dihydrate is 294.10 g/mol. 0.11 mg/mL polysorbate-20 is equivalent to 0.011% w/v. Accordingly, ‘466 teaches compositions having “about” 43.9 mM sodium citrate dihydrate and “about” 0.011% w/v. ‘466 defines the term “about” to mean up to ±10% of the value qualified by this term (Col. 33, lines 15-17). Under this definition, claim 1 of ‘466 encompasses 39.51-48.29 mM sodium citrate and 0.0099%-0.0121% polysorbate-20. Element “a)” of claim 92 recites 50 mM sodium citrate and 0.01% polysorbate-20. The concentration range of polysorbate-20 in ‘466 encompasses 0.01% polysorbate-20 and 48.29 mM sodium citrate is close to 50 mM sodium citrate (MPEP § 2144.05(I)). Thus, claim 92 is prima facie obvious over claim 1 of ‘466.
Regarding claim 93, the claims of ‘466 refer to “velaglucerase”. However, ‘466 defines “velaglucerase” as being a term interchangeable with velaglucerase alfa (col. 36, lines 9-13).
Regarding claim 94, claim 3 of ‘466 teaches reconstitution in sterile water. Thus, there is a reasonable expectation that the pH of the composition is “about 7.0”.
Regarding claims 95 and 99-100, the claims of ‘466 do not teach the specific concentrations and molar ratios recited in these claims. As discussed above, Daniel teaches that IFG provides improved stability and trafficking of the GCB enzyme. Accordingly, a person having ordinary skill in the art would have been expected to have experimented with various amounts and ratios of GCB and IFG when formulating the composition administered in the method of claim 5 of ‘466 and could have arrived at the recited amounts with a reasonable expectation of success. There is no indication that the claimed concentrations and ratios yield an unexpected result.
Regarding claim 96, neither ‘466 nor Daniel teaches a specific temperature for the composition.
Nevertheless, a person having ordinary skill in the art would have been expected to routinely experiment with different temperatures in order to optimize enzymatic efficacy. There would have been a reasonable expectation of success because the claim currently encompasses any temperature.
Alternatively, Do teaches stabilization of the “proper conformation” to increase shelf-life, activity, or in vivo efficacy ([0041]). Do teaches that the stabilization can be observed by greater resistance to unfolding due to temperature increases (Id.). Do demonstrates that when combined with IFG, GCB is properly folded at temperatures of about 40°C (Fig. 8). Accordingly, it would have been obvious to have administered the composition at a temperature of 40°C (a value falling in the range of at least 20°C).
Regarding claim 97, the composition taught by claim 1 of ‘466 comprises sodium citrate dihydrate (i.e., a pharmaceutically acceptable salt).
Claims 78-86, 90, and 92-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 12,286,400 B2 in view of Daniel et al. (US 2011/0027254 A1; cited in IDS filed on 08/09/2023), Do (US 2011/0143419 A1; cited in IDS filed on 08/09/2023), and Schapira (Molecular and Cellular Neuroscience, 2015, Vol. 66, pages 37-42).
The claims of the ‘400 patent are directed to compositions comprising isofagomine and glucocerebrosidase and methods of treating Gaucher disease using the same.
Regarding claims 78 and 83-84, the claims of ‘400 are directed to methods of treating Gaucher disease (i.e., a disorder related to a dysfunction in a GCase pathway) comprising administering a composition comprising glucocerebrosidase and isofagomine in a molar ratio of 1:3 (a range overlapping with the instantly claimed range).
And although the claims of ‘400 do not recite a specific route of administration; Daniel teaches a composition comprising GCB and IFG and teaches that the composition may be injected subcutaneously ([0350]). Accordingly, it would have been obvious to have administered the composition subcutaneously.
As discussed above, the tissue distribution limitation is merely descriptive of an inherent property associated with administration of GCB and IFG. Accordingly, it does not provide a level of non-obviousness sufficient to overcome the teachings of ‘400 in view of Daniel, Do, and Schapira.
Regarding claim 79, as discussed above, Daniel teaches that the composition may be injected subcutaneously ([0350]).
Regarding claim 80, the claims of ‘400 do not specify a particular dosing regimen.
Nevertheless, Daniel teaches that the composition may be administered every week (i.e., once weekly) or every other week (i.e., once every other week)([0009]). Accordingly, it would have been obvious to have administered the same composition once a week or once every other week.
Regarding claims 81 and 98, the claims of ‘400 do not teach that the disorder is a defect in GCase activity. Daniel teaches that Gaucher disease is characterized by a deficiency in glucocerebrosidase (i.e., a decreased enzymatic activity)([0002]). Accordingly, Gaucher disease (taught by claims 15-17 of ‘400) is a disorder comprising a defect in GCase activity.
Regarding claim 82, claims 15-17 of ‘400 are directed to treatment of Gaucher disease but none of the claims teach that the disorder is an alpha-synuclein dysregulation.
Schapira reviews the etiology of Parkinson disease (PD) and provides evidence that Gaucher disease is a disorder comprising alpha-synuclein dysregulation. Specifically, Schapira teaches that GCase metabolizes glucocerebroside to glucose and ceramide and mutations of the GCase GBA1 gene cause Gaucher disease (p. 38, left col., par. 3). Schapira further teaches that the relationship between GCase and alpha-synuclein is reciprocal (i.e., downregulation of GCase leads to increase of alpha-synuclein)(p. 39, Fig. 1). Accordingly, because ‘400 teaches treatment of Gaucher disease (which is related to a downregulation of GCase) and GCase dysfunction is associated with increased (i.e., dysregulated) alpha-synuclein, Gaucher disease is a disorder comprising alpha-synuclein dysregulation.
Regarding claims 85-86, neither ‘400, Daniel nor Do teaches that the methods of ‘400 can be used for treating neurodegenerative disorders such as Parkinson disease, Alzheimer’s disease, and Lewy body dementia.
Nevertheless, as discussed above, Schapira reviews the etiology of Parkinson disease (PD). Schapira teaches that GCase metabolizes glucocerebroside to glucose and ceramide and mutations of the GCase GBA1 gene cause Gaucher disease (p. 38, left col., par. 3). Schapira further teaches that the relationship between GCase and alpha-synuclein is reciprocal (i.e., downregulation of GCase leads to increase of alpha-synuclein)(p. 39, Fig. 1). Schapira teaches that “it is clear that the presence of a GBA mutation in homozygous or heterozygous form is associated with an approximately 20-fild increase in the risk for PD” (abstract) and that there are several candidate pathways through which GCase deficiency may promote pathogenesis of PD, including reciprocal alpha-synuclein levels, lysosomal dysfunction, ERAD, calcium dysregulation, and mitochondrial abnormalities (p. 40, right col., par. 2). Schapira further teaches that “improving the trafficking of mutant GCase by chaperones may enhance GCase not only by lysosomal localization but also by upregulation and reducing the interaction of GCase with alpha-synuclein will increase turnover of alpha-synuclein and reduce its propensity to aggregate (p. 40, right col., par. 4). Schapira concludes that targeting the GCase-lysosomal pathway is an opportunity for development of neuroprotective drugs in PD (p. 40, right col., par. 5).
Accordingly, because ‘400 teaches enzyme therapy for the treatment of Gaucher disease and Schapira teaches that GCase dysfunction associated is intimately linked with the pathogenesis of Parkinson disease, it would have been obvious to have modified the methods of claims 15-17 of ‘400 such that they are instead directed to treatment of Parkinson disease.
Regarding claim 90, the claims of ‘400 do not teach the specific effect recited in this claim. Nevertheless, Daniel teaches that IFG selectively binds to and stabilizes GCB and facilitates proper trafficking of the enzyme to lysosomes ([0326). Daniel further teaches that glucocerebroside (i.e., the target of GCB) is in the spleen and liver (among other locations)([0337]). Accordingly, Daniel teaches that the exposure, activity, and bioavailability (as a result of the improved stability and trafficking) in the spleen and liver is increased and it would have been obvious to have modified the claim to be directed to increasing exposure, activity, or bioavailability of the GCB in the spleen, and/or liver, and/or serum.
Regarding claim 92, claim 10 of ‘400 teaches incorporation of sodium citrate and polysorbate-20. However, the claims of ‘400 do not teach the specific concentrations of sodium citrate/sodium phosphate and polysorbate-20 recited in the instant claim. Nevertheless, a person having ordinary skill in the art would have been expected to have experimented with various amounts of acid salt and polysorbate when formulating the composition administered in the methods of ‘400 and could have arrived at the recited amounts with a reasonable expectation of success. There is no indication that the claimed concentrations and ratios yield an unexpected result.
Regarding claim 93, claim 7 of ‘400 teaches that the GCB is velaglucerase alfa.
Regarding claim 94, neither ‘400 nor Daniel teaches a specific pH.
However, as discussed above, Daniel teaches reconstitution of the velaglucerase with water ([0011], [0033], and [0309]). Thus, there is a reasonable expectation that the pH of Daniel’s composition is “about 7.0”.
Regarding claims 95 and 99-100, the claims of ‘400 do not teach the specific concentrations and molar ratios recited in these claims. As discussed above, Daniel teaches that IFG provides improved stability and trafficking of the GCB enzyme. Accordingly, a person having ordinary skill in the art would have been expected to have experimented with various amounts and ratios of GCB and IFG when formulating the composition administered in the methods of claim 15-17 of ‘400 and could have arrived at the recited amounts with a reasonable expectation of success. There is no indication that the claimed concentrations and ratios yield an unexpected result.
Regarding claim 96, neither ‘400 nor Daniel teaches a specific temperature for the composition.
Nevertheless, a person having ordinary skill in the art would have been expected to routinely experiment with different temperatures in order to optimize enzymatic efficacy. There would have been a reasonable expectation of success because the claim currently encompasses any temperature.
Alternatively, Do teaches stabilization of the “proper conformation” to increase shelf-life, activity, or in vivo efficacy ([0041]). Do teaches that the stabilization can be observed by greater resistance to unfolding due to temperature increases (Id.). Do demonstrates that when combined with IFG, GCB is properly folded at temperatures of about 40°C (Fig. 8). Accordingly, it would have been obvious to have administered the composition at a temperature of 40°C (a value falling in the range of at least 20°C).
Regarding claim 97, claim 10 of ‘400 comprises sodium citrate (i.e., a pharmaceutically acceptable salt).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GRANT C CURRENS/Examiner, Art Unit 1651
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