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 .
Election/Restrictions
The claims remain examined pursuant to applicant’s election, without traverse, of Group I (claims 1-14) in the reply filed on 08/01/2025.
Claims 15-16 and 18-22 remain withdrawn as they are directed to the nonelected invention there being no allowable generic or linking claim.
Claims 1-4 and 6-14 are directed to the elected invention and have been examined on their merits.
Amendments
Claims 1 and 7-10 have had minor typographic changes.
Drawings
Previous objection to the drawings
The drawings were previously objected to because the text in Figure 14A was too small to be readable when reproduced. Applicant has filed an amended drawing sheet which corrects this deficiency.
Accordingly, the objection to the drawings is withdrawn and the drawings filed 02/24/2026 are accepted.
Claim Objections
Previous objections to the claims
Claims 1 and 7 were objected to for minor informalities. Applicant has made the appropriate correction. Therefore, the objections have been withdrawn.
Claim Interpretation
Claim 1 recites a ratio of three components with the approximation “about”. The specification defines this term as meaning as much as ± 20% difference from the recited value (p. 11, lines 12-17). This definition has been applied to the term “about” in the claims.
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 rejections under 35 U.S.C. § 103
RE: Rejection of claims 1-3 and 6-8 under 35 U.S.C. 103 as being unpatentable over Sun et al. (Molecular Genetics and Metabolism, 2018, Vol. 123, Issue 2, pages S137-S138) in view of Qi et al. (Cancer Therapy: Preclinical, 2009, Vol. 15(18), pages 5840-5851).
Applicant traverses the rejection of record by arguing that Sun does not teach any molar ratio of SapC:DOPS or SapC:DOPS:GCase, nor any suggestion of the ranges recited in the claims. In contrast, applicant asserts that the ratio of about 0.1 mM SapC : about 0.7-0.9 mM DOPS : about 1.3 µM GCase is “critical to maximizing stability, uptake, binding affinity, and functional delivery to the brain” (Remarks, p. 7, par. 3). Applicant further asserts that Qi does not supply any missing ratio teaching relevant to the present invention because Qi is for using SapC:DOPS nanovesicles for tumor targeting and apoptosis induction and have no relationship to enzyme loading.
Applicant substantiates this argument by stating that a finding of obviousness based on routine optimization requires that the prior art disclose either (i) the claimed range, (ii) a broader range, or (iii) at least a recognized relationship between variables.
Applicant’s argument has been fully considered but is not sufficient to overcome the rejection of record for the following reasons.
First, the Examiner acknowledges that the prior art is silent as to the specific ratios recited in the instant claims. Nonetheless, Sun’s composition was clearly mixed at some undisclosed ratio. Therefore, the relevant question in the obviousness analysis is if a person having ordinary skill in the art could have arrived at the recited ratio through routine optimization with a reasonable expectation of success and if so, whether this range is critical. For example, would a person having ordinary skill in the art have merely combined the three components taught by Sun in an arbitrary amount when practicing Sun’s invention or would they have routinely optimized the ratio of the three components to maximize the properties of the composition. As discussed in the rejection of record, a person having ordinary skill in the art would have been guided by Sun’s teachings that the SapC-DOPS system significantly increased the activity of GCase when compared to non-nanovesicle-based GCase (p. S137, right col., par. 5). And to the extent that Qi is relevant to this analysis, it is merely used to provide evidence that ordinary artisans do, in fact, experiment with various ratios of SapC-DOPS in order to improve the properties of such compositions. For at least these reasons, the examiner maintains that a prima facie case of obviousness through routine optimization was properly established in the rejection of record.
Because a prima facie case has been established, the next analysis is whether applicant has sufficiently demonstrated (i) that the range is critical, (ii) that the prior art teaches away, (iii) that the claimed parameter was not recognized as “result-effective”, or (iv) that the claimed parameter is disclosed in a very broad range (MPEP § 2144.05(III)(A-D)). Applicant has not argued elements (ii)-(iv). Applicant has, however, attempted to overcome the obviousness rejection by stating that the recited ratio is “critical to maximizing stability, uptake, binding affinity, and functional delivery to the brain” (Remarks, p. 7, par. 3). Showing that a claimed range is “critical to maximizing” a parameter is not particularly compelling because it is merely descriptive of the precise routine optimization discussed in the rejection of record. Example 12 of applicant’s disclosure involves testing various GCase concentrations versus fixed ratios of SapC : DOPS and then various SapC:DOPS ratios with 1.3 µM GCase (summarized in Figures 15-16). Although the optimization may have resulted in “maximizing” the discussed parameters, that does not mean that the range is critical. For example, applicant’s example shows activity in all amounts of GCase tested and in all SapC-DOPS ratios tested with the fixed GCase concentration (Figure 15). The ratios shown in Table 2 of Fig. 15 are considered to be representative of the recited ranges of ratios (under the special definition of “about”) but applicant has not shown that activity is absent or otherwise significantly different outside of these specific ranges. To the contrary, when SapC-DOPS was held at 0.1 : 0.9 mM and GCase was varied, 0.7 and 1.0 µM also had activity which merely differs in degree not kind. Demonstrating criticality should show that the range achieves unexpected results such as by showing a difference in kind rather than degree (MPEP § 2144.05(III)(A)).
Moreover, if the recited ratio is actually critical for stability, uptake, binding affinity, and functional delivery (a point which the examiner does not concede), then Sun must necessarily have used the same ratio because it reported “a safe CNS-targeting system” which “effectively delivers functional GCase without modifications into brain cells and tissues for correction of GCase deficiency” (p. S137, right col., par. 5) and taught that “SapC-DOPS has benefits in protecting GCase function, supplying functional GCase in brain and efficacy in GD mouse model” (p. S138, left col., par. 1).
For at least these reasons, the rejection of record must be maintained.
RE: Rejection of claims 1-4 and 6-8 under 35 U.S.C. 103 as being unpatentable over Sun et al. (Molecular Genetics and Metabolism, 2018, Issue 2, Vol. 123, pages S137-S138) in view of Qi et al. (Cancer Therapy: Preclinical, 2009, Vol. 15(18), pages 5840-5851), as evidenced by Tamargo et al. (Molecular Genetics and Metabolism, 2012, Vol. 106(3), pages 257-263) and Romero et al. (PNAS, 2019, Vol. 116, No. 11, pages 5086-5095).
Applicant traverses the rejection of record by arguing that neither Tamargo nor Romero provide insight as to the specific ratios which would render obvious claim 1.
For at least the reasons discussed above, the rejection over Sun in view of Qi properly establishes motivation to routinely optimize the molar ratio of the SapC:DOPS:GCase composition disclosed by Sun.
For at least these reasons, the rejection of record must be maintained.
RE: Rejection of claims 1-3 and 6-13 under 35 U.S.C. 103 as being unpatentable over Sun et al. (Molecular Genetics and Metabolism, 2018, Vol. 123, Issue 2, pages S137-S138) in view of Qi et al. (Cancer Therapy: Preclinical, 2009, Vol. 15(18), pages 5840-5851) and Crombez (US 2015/0071907 A1; cited in IDS filed on 09/20/2022).
Applicant traverses the rejection of record by arguing the following.
First, applicant asserts that Crombez does not provide insight as to the tri-component ratio optimization for lipid-base carriers.
Second, applicant asserts that Crombez does not suggest moving away from free, soluble enzymes to SapC-DOPS vesicles. And, if anything, Crombez would dissuade a person having skill in the art from arriving at the claimed approach.
Third, applicant argues that Crombez is used through impermissible hindsight.
Fourth, applicant asserts that Crombez is non-analogous because it is not about nanovesicles and is therefore a different field and a different problem.
Applicant’s arguments have been fully considered but are not sufficient to overcome the rejection of record for the following reasons.
With respect to the first argument, for at least the reasons discussed above, the rejection over Sun in view of Qi properly establishes motivation to routinely optimize the molar ratio of the SapC:DOPS:GCase composition disclosed by Sun.
With respect to the second argument, Crombez is relied upon only to demonstrate that types 2 and 3 Gaucher Disease are neuronopathic Gaucher Diseases and to demonstrate why it would have been obvious to have modified Sun’s method of treating neuronopathic Gaucher Disease such that it is more narrowly directed to treating types 2 or 3 Gaucher Disease. Therefore, it is not particularly relevant that Crombez uses a different composition in glucocerebrosidase replacement because that is not what is relied upon for the rejection.
With respect to the third argument, "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper” (MPEP § 2145(X)(A)). In this case, the consideration of the prior art was not based upon applicant’s disclosure. Instead, Sun’s disclosure was assessed in light of what was known in the art at the time of filing. That is to say, it was known at the time of filing (i) that SapC:DOPS:GCase compositions could treat neuronopathic Gaucher Disease and (ii) that Types 2 and 3 are types of neuronopathic Gaucher Disease which are typically treated through GCase replacement. Therefore, it would have been obvious to have used Sun’s composition in a method of treating types 2 and 3 Gaucher Disease because these are conditions typically treated with GCase replacement. This analysis clearly does not rely on applicant’s disclosure.
With respect to the fourth argument, while applicant contends that the problem cannot be defined so generally that any Gaucher document qualifies (Remarks, p. 11, par. 3), the Examiner instead contends that it is improper to define the problem so narrowly that only disclosures of compositions comprising SapC:DOPS:GCase are relevant to an obviousness analysis in this case. A person having ordinary skill in the art would not have limited their assessment only to methods of treating types 2 and 3 Gaucher Disease with SapC:DOPS:GCase when determining whether it is obvious to modify Sun’s methods in this way. Therefore, applicant’s argument that Crombez is non-analogous merely because it “it is not about nanovesicles” (Remarks, p. 11, par. 3) is not compelling. Crombez is clearly analogous because it directly addresses the conventional use of GCase replacement therapy in type 2 and type 3 Gaucher Disease and provides a teaching that neuronopathic Gaucher Disease can be treated by delivering an enzyme replacement (in this case, GCase) across the blood-brain barrier. Thus, it would have been abundantly obvious to use Sun’s GCase composition (which is taught to effectively cross the blood-brain barrier) in the treatment of types 2 and 3 Gaucher Disease.
For at least these reasons, the rejection of record is proper and has been maintained.
RE: Rejection of claims 1-3 and 6-14 under 35 U.S.C. 103 as being unpatentable over Sun et al. (Molecular Genetics and Metabolism, 2018, Vol. 123, Issue 2, pages S137-S138) in view of Qi et al. (Cancer Therapy: Preclinical, 2009, Vol. 15(18), pages 5840-5851), Crombez et al. (US 2015/0071907 A1; cited in IDS filed on 09/20/2022) and Narita et al. (Annals of Clinical and Translational Neurology, 2016, Vol. 3(3), pages 200-215).
Applicant traverses the rejection of record by arguing that neither Crombez nor Narita provide insight as to the specific ratios which would render obvious claim 1.
For at least the reasons discussed above, the rejection over Sun in view of Qi properly establishes motivation to routinely optimize the molar ratio of the SapC:DOPS:GCase composition disclosed by Sun.
The examiner disagrees with applicant’s assertion that “such ratio is a result-effective variable whose tuning would predictably control enzyme binding, activity retention, vesicle stability, or biodistribution” (Remarks, p. 13, par. 2). As discussed above, applicant is attempting to overcome a rejection for routine optimization by arguing that they have experimented to “maximize” the properties of Sun’s composition (i.e., applicant has performed the precise optimization contemplated in the rejection of record). Sun previously disclosed that SapC-DOPS could protect GCase function, increase GCase delivery, and improve distribution. Applicant has not met their burden for establishing that the recited ratio is critical or that it changes anything more than the degree of activity. Moreover, because Sun’s methods have the same result (protection of function, improvement of GCase delivery, and improved distribution), then applicant either experimented and arrived at the exact ratio used by Sun or the recited ratio is not critical as alleged. In both cases, the ratio is obvious through routine experimentation because they both fundamentally rely on the use Sun’s composition in Sun’s method and the only change is experimentation to “maximize” the previously disclosed properties of the composition.
For at least these reasons, the rejection of record must be maintained.
Maintained rejections under 35 U.S.C. § 103
Claims 1-3 and 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Sun et al. (Molecular Genetics and Metabolism, 2018, Vol. 123, Issue 2, pages S137-S138) in view of Qi et al. (Cancer Therapy: Preclinical, 2009, Vol. 15(18), pages 5840-5851).
Sun et al. (hereinafter Sun) is a published conference abstract from the 2018 WORLDSymposium™. Sun teaches that enzyme replacement therapy (ERT) is a conventional care for Gaucher Disease (GD)(p. S137, right col., par. 5). However, ERT is not effective to the highly symptomatic and lethal form of GD affecting the central nervous system (CNS)(Id.). In order to address the CNS-affecting GD types, Sun reports the development of a non-invasive CNS delivery system for GCase using SapC-DOPS nanovesicles that consist of saposin C (SapC) and dioleoylphosphatidylserine (DOPS)(Id.).
Regarding claim 1, Sun teaches a nanovesicle comprising saposin C (SapC) and dioleoylphosphatidylserine (DOPS)(SapC-DOPS), which provides a “safe CNS-targeting system and effectively delivers functional GCase without modifications into brain cells and tissues for correction of GCase deficiency” (Id.).
With respect to the composition comprising acid β-glucosidase (GCase), Sun teaches that human GCase (velaglucerase alfa) was delivered by the SapC-DOPS nanovesicles and increased activity 4 to 15-fold for up to 48 hours when compared to non-nanovesicle based GCase in GCase-deficient mice and neuronopathic GD patient-derived fibroblasts (Id.).
Thus, Sun teaches a method of administering to a subject an effective amount of a composition comprising SapC, DOPS, and GCase.
With respect to the recited SapC, DOPS, and GCase ratio of about 0.1 mM SapC : about 0.7 mM to about 0.9 mM DOPS : about 1.3 µM GCase, Sun does not teach the specific ratio of SapC to DOPS to GCase.
Nonetheless, a person having ordinary skill in the art could have arrived at the recited ratio as a result of routine experimentation. As discussed above, the prior art previously disclosed a composition comprising SapC, DOPS, and GCase. And although Sun does not teach the recited ratios of each component, it would have been obvious to have performed routine experimentation with various ratios of the components in order to arrive at the instantly claimed range. Qi et al. demonstrates the routine nature of such experimentation by disclosing ratio-altering experimentation when formulating SapC-DOPS in order to maximize cytotoxicity against human neuroblastoma (p. 5843, left col., par. 4; Fig. 1A). Thus, a person having ordinary skill in the art would have been prompted to perform similar experimentation when formulating the nanovesicle disclosed by Sun in order to, for example, optimize the stability or efficacy of Sun’s treatment. There would have been a reasonable expectation of success because the experimentation merely requires incorporating various amounts of each component and testing their ability to treat Gaucher Disease and because Qi demonstrates the routine nature of such experimentation when optimizing the cytotoxic effect of the same composition. Generally, differences in concentration 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)). In this case, there is no evidence of record that demonstrates that the recited molar ratio elicits an unexpected or remarkable result.
With respect to the method being for treating a subject suffering from Gaucher Disease, Sun teaches that the SapC-DOPS-GCase nanovesicle has benefits in protecting GCase function, supplying functional GCase in brain and efficacy in GD mouse model (p. S138, left col., par. 1). Moreover, Sun teaches that the “novel CNS-ERT approach directly addresses the unmet medical needs of neuronopathic GD patients and may have therapeutic potential for other lysosomal diseases with CNS involvement”.
Thus, although Sun does not directly teach a “method of treatment” using this system, it clearly suggests the potential of a SapC-DOPS-GCase nanovesicle to treat a subject suffering from Gaucher Disease. There would have been a reasonable expectation of success because Sun teaches that ERT is a “conventional care” for Gaucher Disease and teaches the potential of the SapC-DOPS-GCase nanovesicle to treat the neuronopathic aspects of GD. 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 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 step of administering to the subject an effective amount of the composition, Sun does not teach administration of any particular amount of the nanovesicle, however, it would have been obvious to have administered “an effective amount” of the prior art composition in order to achieve the effect of treating GD.
Thus, claim 1 is obvious over Sun in view of Qi as a result of routine experimentation.
Regarding claim 2, as discussed above, Sun discloses the use of a SapC-DOPS-GCase nanovesicle.
Regarding claim 3, as discussed above, Sun in view of Qi renders obvious the method of claim 1 including administering a nanovesicle comprising SapC, DOPS, and GCase.
For the same reasons discussed above, it would have been obvious to have routinely experimented with various relative concentrations (e.g., molar ratios) SapC and DOPS to arrive at a molar ratio of about 1:7, as claimed.
A person having ordinary skill in the art, when formulating and using the method rendered obvious by Sun would have been expected to routinely experiment with various ratios of the components in order to optimize the stability and efficacy of the treatment in a subject having GD. There would have been a reasonable expectation of success because the modification merely requires incorporating various amounts of both components and testing their ability to treat Gaucher Disease and because Qi demonstrates the routine nature of such experimentation with SapC-DOPS vesicles. Generally, differences in concentration 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)). In this case, there is no evidence of record that demonstrates that the recited molar ratio elicits an unexpected or remarkable result.
Regarding claim 6, as discussed above, Sun in view of Qi renders obvious the method of claim 1 including administering a nanovesicle comprising SapC, DOPS, and GCase.
Sun teaches that the composition can be administered intravenously (p. S137, right col., par. 6).
Regarding claim 7, as discussed above, Sun in view of Qi renders obvious the method of claim 1 including administering a nanovesicle comprising SapC, DOPS, and GCase.
Sun teaches that when the SapC-DOPS-GCase nanovesicle was administered in vivo, GCase was detected in neurons, microglia, astrocytes and was distributed in the cortex, midbrain, brain stem, thalamus, and CNS lymphatic system (Id.). Thus, the composition crosses a blood-brain barrier of the subject.
Regarding claim 8, as discussed above, Sun in view of Qi renders obvious the method of claim 1 including administering a nanovesicle comprising SapC, DOPS, and GCase.
Sun teaches that the composition “directly addresses the unmet medical needs of neuronopathic GD patients (Id.; emphasis added). Thus, Sun renders obvious a method of treating neuronopathic Gaucher Disease (nGD).
Claims 1-4 and 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Sun et al. (Molecular Genetics and Metabolism, 2018, Issue 2, Vol. 123, pages S137-S138) in view of Qi et al. (Cancer Therapy: Preclinical, 2009, Vol. 15(18), pages 5840-5851), as evidenced by Tamargo et al. (Molecular Genetics and Metabolism, 2012, Vol. 106(3), pages 257-263) and Romero et al. (PNAS, 2019, Vol. 116, No. 11, pages 5086-5095).
The teachings of Sun and Qi are set forth above and applied herein. Sun in view of Qi is found to render obvious claims 1-3 and 6-8.
Regarding claim 4, as discussed above, Sun in view of Qi renders obvious the method of claim 1. Specifically, Sun renders obvious the administration of a composition comprising SapC, DOPS, and GCase in the recited molar ratio for the treatment of Gaucher Disease.
Sun teaches that SapC-DOPS system protects the GCase function (p. S138, left col., par. 1) but does not teach that the GCase is bound to SapC in the presence of DOPS via non-covalent interactions selected from the group consisting of hydrophobic interactions, van der Waals forces, and combinations thereof.
Tamargo et al. (hereinafter Tamargo) teaches that SapC has particular relevance for Gaucher Disease because it is a necessary activator for GCase (p. 258, left col., par. 2). SapC is capable of penetrating phospholipid membrane and binding anionic phospholipids (p. 259, left col., par. 3). Two polypeptide fragments of SapC are known to each individually promote GCase activity to 90% of control levels (p. 259, left col., par. 4). Tamargo teaches that the preferred theory for SapC-GCase association is that SapC remains bound to thinned regions of a membrane where glycosphingolipids are exposed and GCase associates with this complex and cleaves exposed glucosylceramide headgroups that sit above the thinned portions of the membrane (i.e., the “liftase” model)(p. 259, right col., par. 4; p. 260, Fig. 3). Additionally, SapC also protects GCase from proteolytic degradation (p. 259, right col., par. 5).
And although Tamargo teaches that GCase “associates” with SapC, it does not teach that this interaction is by hydrophobic or van der Waals forces.
Romero et al. (hereinafter Romero) also studies the interactions between SapC and GCase and teaches that in the active complex, the W348 sidechain of GCase (located in loop 2) is tucked into a hydrophobic pocked formed by SapC (p. 5088, right col., par. 2; Fig. 3B; p. 5092, right col., par. 3).
Thus, because Sun teaches a nanovesicle comprising DOPS, SapC, and GCase and because Tamargo and Romero provide evidence that in the presence of an anionic (i.e., negatively charged) lipids, GCase associates with SapC by binding a hydrophobic pocket, there is a reasonable expectation that the GCase in Sun’s method is bound to SapC in the presence of DOPS via non-covalent interactions selected from the group consisting of hydrophobic interactions, van der Waals forces, and combinations thereof because this is a property inherent to GCase and SapC when in the presence of negatively charged lipids (e.g., DOPS). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference (MPEP § 2112(II)).
Thus, claim 4 is obvious over Sun in view of Qi, as evidenced by Tamargo and Romero.
Claims 1-3 and 6-13 are rejected under 35 U.S.C. 103 as being unpatentable over Sun et al. (Molecular Genetics and Metabolism, 2018, Vol. 123, Issue 2, pages S137-S138) in view of Qi et al. (Cancer Therapy: Preclinical, 2009, Vol. 15(18), pages 5840-5851) and Crombez (US 2015/0071907 A1; cited in IDS filed on 09/20/2022).
The teachings of Sun and Qi are set forth above and applied herein. Sun in view of Qi is found to render obvious claims 1-3 and 6-8.
Regarding claim 9, as discussed above, Sun in view of Qi renders obvious a method of treating neuronopathic Gaucher Disease with a SapC-DOPS-GCase nanovesicle.
However, neither Sun nor Qi teaches that the neuronopathic Gaucher Disease is type 2 or type 3 Gaucher Disease.
Nonetheless, Crombez et al. (hereinafter Crombez) teaches compositions and methods for treating type 3 Gaucher Disease ([0005]). Crombez teaches that the treatment methods are based upon the premise that glucocerebrosidase replacements can cross the blood-brain barrier and thus can be used to treat or prevent or prevent progression of the neurological parameters and symptoms associated with type 3 Gaucher Disease ([0005]). Crombez teaches that Gaucher Disease is the most common lysosomal storage disease and is caused by a hereditary deficiency in glucocerebrosidase (i.e., acid β-glucosidase)([0343]). Type 2 Gaucher Disease is an acute infantile neuropathic Gaucher Disease ([0346]) and type 3 Gaucher Disease is the chronic neuropathic form and is characterized by slowly progressive but milder neurological symptoms compared to acute or type 2 Gaucher Disease ([0347]).
Thus, because Sun in view of Qi renders obvious a method of treating neuronopathic Gaucher Disease by administering SapC-DOPS-GCase nanovesicles and Crombez teaches that types 2 and 3 Gaucher Disease are neuronopathic Gaucher Diseases which can be treated by enzyme replacement with components which can cross the blood-brain barrier, it would have been obvious to have further modified Sun’s method such that the type of Gaucher Disease which is treated with the SapC-DOPS-GCase liposome is type 2 or type 3 Gaucher Disease. There would have been a reasonable expectation of success because it was previously known that types 2 and 3 Gaucher Disease were characterized by a deficiency in β-glucosidase and because both Sun and Crombez teach that neuronopathic Gaucher Disease can be treated by delivering an enzyme replacement (in this case, GCase) across the blood-brain barrier. This obviousness is based upon the “Some Teaching, 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 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, claim 9 is obvious over Sun in view of Qi and Crombez.
Regarding claims 10-11, as discussed above, Sun in view of Qi renders obvious a method of treating neuronopathic Gaucher Disease with a SapC-DOPS-GCase nanovesicle.
However, neither Sun nor Qi teaches that the method further comprises administering a second therapeutic agent effective for the treatment of Gaucher Disease.
Nonetheless, Crombez teaches treating Gaucher Disease by administering a glucocerebrosidase enzyme replacement therapy such as imiglucerase or velaglucerase ([0006]-[0007]). Crombez further teaches that in some aspects, the enzyme replacement therapy is used in combination with another agent such as isofagomine tartrate (i.e., a pharmacological chaperone; see [0333] for support), miglustat (i.e., a substrate reduction therapy), or Genz112638 ([0170]).
As such, it would have been obvious to have further modified the method of Sun such that the method further comprises administering a second therapeutic agent effective for the treatment of Gaucher Disease. For example, it would have been particularly advantageous to have further administered an additional enzyme replacement therapy (such as imiglucerase or velaglucerase) as this is “conventional care” (Sun, S137, right col., par. 6) or further included the combination of a pharmacological chaperone or substrate reduction therapy in combination with the SapC-DOPS-GCase agent. The proposed modification would have predictably resulted in a more effective Gaucher Disease therapy by providing more compositions which were previously known to be useful in the treatment of this disease. 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 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 10-11 are obvious over Sun in view of Qi and Crombez.
Regarding claim 12, as discussed above, it would have been obvious to have used an additional enzyme replacement therapy. As discussed above, Crombez teaches the use of imiglucerase and/or velaglucerase alfa for treatment of Gaucher Disease. As such, it would have been obvious for the additional enzyme replacement therapy to be one of these compositions.
Regarding claim 13, as discussed above, it would have been obvious to have used an additional substrate reduction therapy. As discussed above, Crombez teaches the use of miglustat for treatment of Gaucher Disease. As such, it would have been obvious to have used miglustat as a second therapeutic agent.
Claims 1-3 and 6-14 are rejected under 35 U.S.C. 103 as being unpatentable over Sun et al. (Molecular Genetics and Metabolism, 2018, Vol. 123, Issue 2, pages S137-S138) in view of Qi et al. (Cancer Therapy: Preclinical, 2009, Vol. 15(18), pages 5840-5851), Crombez et al. (US 2015/0071907 A1; cited in IDS filed on 09/20/2022) and Narita et al. (Annals of Clinical and Translational Neurology, 2016, Vol. 3(3), pages 200-215).
The teachings of Sun, Qi, and Crombez are set forth above and applied herein. Sun in view of Qi and Crombez is found to render obvious claims 1-3 and 6-13.
Regarding claim 14, as discussed above, Sun in view of Qi and Crombez renders obvious a method of treating Gaucher Disease by administering the SapC-DOPS-GCase composition including by administering an additional therapeutic such as a pharmacological chaperone (e.g., isofagomine tartrate).
However, neither Sun, Qi, nor Crombez teaches that the pharmacological chaperone is selected from the group consisting of ambroxol hydrochloride, N-(n-nonyl)deoxynojirimycin (NN-DNJ), and combinations thereof.
Nonetheless, Narita et al. (hereinafter Narita) discloses a pilot study which investigates the use of ambroxol in treatment of neuronopathic Gaucher Disease (abstract). Narita teaches that enzyme-replacement and substrate-reduction therapies are available but their efficacies in treating the neurological manifestations of Gaucher Disease are negligible (Id.). Thus, pharmacological chaperones offer a new strategy for treating the neurological manifestations of this disease (Id.). Narita teaches that ambroxol hydrochloride, a commonly used expectorant, was identified as a pharmacological chaperone and was shown to enhance endogenous GCase activity (abstract; p. 201, left col., par. 3 and right col., par. 3). Narita concludes that ambroxol had good safety and significantly increased lymphocyte glucocerebrosidase activity, permeated the blood-brain barrier, and decreased glucosylsphingosine levels in the cerebrospinal fluids (abstract).
Thus, because Sun in view of Qi and Crombez renders obvious the method of treating Gaucher Disease by administering an additional agent, such as a pharmacological chaperone and because Narita teaches that ambroxol hydrochloride is a GCase chaperone which significantly increases GCase activity and permeates the blood-brain barrier, it would have been obvious to have substituted the pharmacological chaperones taught by Crombez (e.g., the isofagomine tartrate) with another known and effective pharmacological chaperone such as ambroxol hydrochloride. Both components were previously known to be effective chaperones for GCase and the substitution would have predictably resulted in a composition which more effectively treats Gaucher Disease by including a therapeutic that crosses the blood-brain barrier and improves the activity of the GCase. This obviousness is based upon the “Simple Substitution of One Known Element for Another to Obtain Predictable Results” rationale set forth in in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007).
Thus, claim 14 is obvious over Sun in view of Qi, Crombez, and Narita.
Conclusion
No claim is allowed.
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