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 .
Priority
This application is a 371 of PCT/EP2020/069432 filed 07/09/2020. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) based on EP 19305928.4 filed 07/09/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Status of the Claims
Claims 21-26 are amended. Claims 27-38 are new.
Claims 2-10, 12, 13, 17-19 and 21-38 are pending (claims set filed 04/20/2026) and are examined on the merits herein.
Withdrawal of Rejections
The response and amendment filed on 04/20/2026 are acknowledged. All of the amendment and arguments have been thoroughly reviewed and considered.
For the purposes of clarity of the record, the reasons for the Examiner's withdrawal and/or maintaining if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner's response to arguments section.
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 2-10, 12, 13, 17-19 and 21-38 are rejected under 35 U.S.C. 103 as being unpatentable over Puzzo (Puzzo et al. Sci. Transl. Med., 2017, 9, eaam6375, 1-12) in view of Khanna (Khanna et al. PLOS One, 2012, 7, e40776, 1-12) and Lukas (Lukas et al. Molec. Therapy, 2015, 23, 456-464 on record in IDS).
Regarding claims 2-4 and 6-8, Puzzo teaches treatment of glycogen storage disease or Pompe disease with secretable acid-α-glucosidase (GAA) expressed in liver. Puzzo describes using adeno-associated virus (AAV) vector optimized for hepatic expression to deliver the nucleic acid encoding GAA. (Abstract). Puzzo discloses that treatment of knockout (Gaa-/-) mice with the AAV expressing GAA in liver rescued glycogen accumulation in central nervous system (Abstract). Puzzo describes that administration of AAV with hepatically expressed GGA results in uptake of GAA by spinal cord as detected by Western blot analysis of spinal cord lysates 10 months after AAV treatment (p. 4, right column, last paragraph and Figure 4B). Additionally, such treatment resulted in improvement of the survival of motor neurons and neuroinflammation and normalization of astrogliosis in spinal cord (p. 9, right column, 3rd paragraph). Puzzo mentions that even though GAA does not normally cross the blood-brain barrier (BBB), however the high circulating GAA may lead to a leakage across BBB or other mechanisms such as transport via exosomes may be involved (p. 9, right column 4th paragraph).
Puzzo does not teach administration of pharmacological chaperons, i.e. DNJ and ABX, however indicates that combination of enzyme replacement therapy with chaperones leads to stabilization of recombinant GAA and results in greater therapeutic efficacy (p. 9, right column, 3rd paragraph).
Khanna teaches that pharmacological chaperone AT2220 (DNJ, duvoglustat) increases recombinant human GGA (rhGGA) uptake and glycogen reduction in mouse model of Pompe disease (Abstract). Khanna describes that “oral pre-administration of AT2220 to rats led to a greater than two-fold increase in the circulating half-life of intravenous rhGAA. Importantly, co-administration of AT2220 and rhGAA to GAA knock-out (KO) mice resulted in significantly greater rhGAA levels in plasma, and greater uptake and glycogen reduction in heart and skeletal muscles, compared to administration of rhGAA alone.“ (Abstract). Khanna mentions that AT2220 has been shown to bind GAA, increase its stability, lysosomal trafficking and activity and that may explain the increase in the half-life of rhGAA in circulation and uptake of rhGAA by tissues (p. 10, left column, 1st and 2nd paragraphs).
Lukas teaches combination of chaperones that stabilize activity of enzymes of lysosomal storage disorders, i.e. α-galactosidase (for Fabry disease) and α-glucosidase (for Pompe disease). Lucas describes that co-administration of two pharmacological chaperones, DNJ with ABX, led to higher stabilization of α-galactosidase during thermal denaturation than with DNJ alone and that: “ABX alone does not preserve enzyme activity but when used with DGJ has a synergistic positive effect” (p. 458, right column, p. 459, left column, 1st paragraph). Lucas discloses significant increase in the activity of GAA mutants upon administration of DNJ in combination with ABX (p. 459, left column, 2nd paragraph). Lukas mentions that pharmacological chaperones correct misfolding, stabilize protein structure, prevent proteasomal degradation and facilitate transport to lysosome (p. 457, left column, 3rd paragraph). Lukas suggests that combination of chaperones can improve current treatment strategies for Fabry and Pompe diseases (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine teachings of Puzzo and Khanna and co-administer DNJ with GAA treatment taught by Puzzo. One would have been motivated to make this combination since Khanna showed co-administration of rhGAA and DNJ to result in prolonged half-life of GAA in circulation and increase in uptake of GAA by heart and skeletal muscle and Puzzo mentioned that higher level of GAA in circulation may be necessary for its uptake by spinal cord. A skilled artisan would have reasonably expected success in this combination since both Puzzo and Khanna developed methods for treatment of Pompe disease with GAA deficiency by enzyme replacement therapy.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to co-administer ABX with DNJ as described by Lukas for treatment of GSD and CNS disfunction during GSD and to increase the GAA uptake in the spinal cord based on Puzzo and Khanna teachings. One would have been motivated to do that since Lukas showed stabilization of α- galactosidase and enhancement of GAA activity by combination of DNJ and ABX compared to DNJ alone. A skilled artisan would have reasonably expected success in this combination since Puzzo, Khanna and Lukas teach treatment of GSD disease with GAA deficiency.
The recitations “increasing the uptake of a therapeutic acid-alpha glucosidase (GAA) polypeptide in the spinal cord from the circulation” in claims 3 and 7 are interpreted as recitation of intended use. The intended use is given weight to the extent that it imparts a structural limitation and the prior art needs to be capable of performing the intended use. See MPEP 2111.02, section II. In instant case, the prior art renders the instantly claimed method steps obvious, Puzzo teaches uptake of therapeutic GAA in the spinal cord, Khanna showed increase in GAA uptake in heart and muscle in the presence of chaperone DNJ and Lukas showed benefits of combination of ABX and DNJ chaperones. Therefore, the method described in prior art is capable of achieving the same goal, i.e. to increase the uptake of a therapeutic acid-alpha glucosidase (GAA) polypeptide in the spinal cord from the circulation.
The recitations in the wherein clause of claims 2, 4, 6 and 8: “wherein the pharmacological chaperones increase the uptake of the therapeutic GAA polypeptide in the spinal cord from the circulation” are interpreted as recitation of intended use. MPEP 2111.04 states: “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003))”. In instant case, the prior art renders the instantly claimed method steps obvious, Puzzo indicates the necessity of higher amount of circulating GAA to achieve uptake by spinal cord and Khanna demonstrates that co-administration of GAA and chaperone, DNJ, increases the half-life of GAA and hence increases the circulating amount and that will facilitate the uptake of GAA in the spinal cord. Therefore, the method described in prior art is capable of achieving increase in the uptake of a therapeutic GAA polypeptide in the spinal cord from the circulation in the presence of pharmacological chaperones.
Thus, Puzzo, Khanna and Lukas teachings render claims 2-4 and 6-8 obvious.
Regarding claims 9 and 17, Puzzo teaches nucleic acids encoding GAA and viral vectors comprising nucleic acids encoding GAA for transgene delivery (Abstract) and hence Puzzo teaching in combination with Khanna and Lukas teachings renders claims 9 and 17 obvious.
Regarding claims 5, 10 and 19, Puzzo teaches administration of the viral vector with nucleic acid encoding GAA (Abstract). Khanna teaches administration of duvoglustat (Abstract) as described above. Lukas teaches administration of ABX in the form of Ambroxol hydrochloride (p.462. right column, last paragraph). Thus, Puzzo, Khanna and Lukas teachings render claims 5, 10 and 19 obvious.
Regarding claim 12, Puzzo teaches treatment of Pompe disease which is GSDII disease (Abstract). Thus, Puzzo, Khanna and Lukas teachings render claim 12 obvious.
Regarding claims 13 and 18, Khanna teaches co-administration of rhGAA and DNJ chaperone (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that chaperones can be co-administered with the nucleic acid molecule encoding GAA similar to co-administration of DNJ and rhGAA described by Khanna. One would have been motivated to do that since Khanna showed increase in the half-life of GAA in circulation and increase in uptake of GAA by tissues with co-administration of rhGAA and DNJ. Alternatively, one would be motivated to optimize the administration regimen to achieve the highest level of GAA in circulation and tissues. A skilled artisan would have reasonably expected success in that because Puzzo, Khanna and Lukas teach treatment of GSD disease and optimization of administration regimen is within the skill of artisan in the field. Thus, Khanna teaching in combination with Puzzo and Lukas teachings render claims 13 and 18 obvious.
Regarding claims 21-26, Puzzo teaches generation of several AAV vectors encoding truncated GAA under the control of a hepatocyte-specific promoter, hAAT (p. 3, right column, 2nd paragraph). Thus, Puzzo, Khanna and Lukas teachings render claims 21-26 obvious.
Regarding claims 27-32, Puzzo teaches AAV8 vectors and mentions that they are efficient for liver gene transfer (p. 2, left column, 3rd paragraph). Thus, Puzzo, Khanna and Lukas teachings render claims 27-32 obvious.
Regarding claims 33-38, Puzzo teaches development of several construct encoding GAA to increase therapeutic efficacy. The constructs contained codon-optimized version of DNA encoding human GAA with truncations (sp2-∆8co and sp7-∆8co). Analysis of expressed GAA activity in vitro in HuH7 cells showed higher GAA activity for the modified constructs compared to the wild-type GAA activity (p. 2, left column, 4th and 5th paragraphs and Figure 1a and B). GAA activity was measured by hydrolysis of an artificial substrate, 4-methyl-umbelliferyl-α-D-glucoside (as Puzzo refers to Amalfitano et al. PNAS, 1999, 96, 8861-8866) and not with natural GAA substrate, glycogen. However, in vivo experiments of AAV-mediated gene transfer of engineered GAA to mouse liver showed higher reduction in glycogen in muscles for modified constructs (sp2-∆8co and sp7-∆8co) compared to the construct encoding wild-type GAA indicating higher therapeutic efficacy (p. 3, Fig. 2C and p. 4, left column, last paragraph). Since reduction of glycogen is due to hydrolyzing activity of GAA, results of in vivo experiments of Puzzo indicate that the hydrolyzing activity of therapeutic GAA on glycogen was higher than 80% of the wild-type activity. Therefore, Puzzo, Khanna and Lukas teachings render claims 33-38 obvious.
Response to Arguments
Applicant's arguments filed 04/20/2026 have been fully considered but they are not persuasive.
Applicant argues (addressing p. 11 of the Remarks) that Khanna teaches that it is unlikely that DNJ increases rhGAA penetration into the CNS and therefore it is unlikely that coadministration of DNJ and rhGAA would increase the uptake of therapeutic GAA in the CNS, such as spinal cord. These arguments are not persuasive because:
Although Khanna did not show increase in the uptake of GAA by CNS, Khanna teaches that DNJ binds exogenous GAA significantly increasing its stability and preventing denaturation in human blood ex vivo (p. 10, left column, 1st paragraph) and similarly co-administration of rhGAA and DNJ prolongs the half-life of GAA in circulation (p. 10, left column, 2nd paragraph). Puzzo teaches uptake of hepatically expressed GAA by spinal cord (p. 4, right column, last paragraph and Figure 4B) and improvement of the survival of motor neurons and neuroinflammation and normalization of astrogliosis in spinal cord (p. 9, right column, 3rd paragraph) and suggest that even though GAA does not normally cross the blood-brain barrier (BBB), however the high circulating GAA may lead to a leakage across BBB or other mechanisms such as transport via exosomes may be involved (p. 9, right column 4th paragraph). That provides motivation for co-administration of DNJ with GAA to increase GAA level in circulation following Khanna teaching and thus provide uptake by CNS such as spinal cord based on Puzzo teaching.
Applicant argues (addressing p. 11 of the Remarks) that Lukas shows that coadministration of ABX and DNJ enhances GAA activity of certain mutant in vitro and concludes that the success of combined administration with ABX strongly depends on the chaperone used and the type of mutation. Applicant further argues that “Lukas failed to demonstrate or even discuss the effects of the chaperones on wild-type GAA activity” and demonstrates in previously cited WO 2013091897 on Figure 7 that coadministration of ABX and NB-DNJ actually reduced the enzymatic activity of the wild-type GAA. Applicant notes that the data presented in Figure 7 in WO 2013091897 are the same as in Figure 3 of Lukas cited in the rejection and one of ordinary skill in the art would not be motivated to co-administer ABX and NB-DNJ with therapeutic GAA. Applicant mentions that: “Because NB-DNJ and DNJ have similar outcomes when used as a monotherapy, one of ordinary skill in the art would have reasonably expected that both chaperones would have a similar effect on the wild-type GAA when administered in combination with ABX, i.e., reducing the wild-type GAA activity.” Applicant argues that: “Contrary to the teachings of the cited art, the present application demonstrates a synergistic effect of the combined administration of DNJ and ABX to enhance gene therapy efficacy, particularly in increasing the levels of GAA in spinal cord.” Applicant adds that “a therapeutic GAA polypeptide” would have wild-type GAA characteristics, which the mutants used in Lukas do not possess.” These arguments are not persuasive because:
First, Examiner acknowledges that Figs. 3A and 3B of Lukas present the same data as reported earlier in WO 2013091897 on Figs. 7A and 7B with some differences in statistical evaluation. Figs. 3A and 3B present data on GAA activity in HEK-293H cells expressing the same mutants of GAA treated with chaperones. Figs. 3A and 7A show results for chaperones ABX, NB-DNJ and NB-DNJ/ABX combination and Figs. 3B and 7B for DNJ and DNJ/ABX combination. The data for the wild-type GAA are shown on Fig. 7A only and does show reduction in GAA activity for NB-DNJ and NB-DNJ/ABX combination, however, that reduction is not marked as statistically significant. Besides, although NB-DNJ is a derivative of DNJ, they may not have similar outcome as suggested by Applicant. As can be seen from Fig. 3A and 3B combination of NB-DNJ/ABX not significantly enhances GAA activity for GAA mutants p.Y455F and p.P545L in comparison with NB-DNJ monotherapy, while GAA activity of the same mutants is significantly and synergistically increased by combination treatment of DNJ-ABX in comparison to DNJ alone or ABX alone. Lukas mentions that effect of combined treatment strongly depends on chaperone used (p. 459, right column, 1st paragraph). Therefore, in cannot be excluded that DNJ in combination with ABX can have different effect that NB-DNJ on the therapeutic GGA with wild-type characteristics. It is also noted that only DNJ and not its derivative NB-DNJ was used in instant working examples and synergistic increase of the GAA in spinal cord is shown at treatment with DNJ and ABX.
Second, besides synergistic increase of GAA activity of mutant GAA by treatment with combination of DNJ and ABX, Lukas teaches synergistic positive effect of co-administration of DNJ with ABX on stabilization of another lysosomal enzyme α-galactosidase during thermal denaturation (p. 458, right column, p. 459, left column, 1st paragraph, Figure 2). Lukas mentions that lysosomal hydrolases share common structural and functional features (p. 457, left column, 2nd paragraph). Lukas proposes to use ABX as enhancer of chaperone action for treatment of lysosomal storage diseases, including Fabry disease caused by α-galactosidase and Pompe disease caused by deficiency of GAA (Abstract). Therefore, Puzzo indicates that combination of enzyme replacement therapy with chaperones leads to longer half-life of the stabilized recombinant GAA and results in greater therapeutic efficacy (p. 9, right column, 3rd paragraph), Khanna teaches DNJ to increase stability and prevent denaturation of GAA and prolong its half-life of in circulation as described above and Lukas suggests to add ABX to DNJ chaperone for therapeutic treatment and shows synergistic action of DNJ and ABX. That provides motivation to add both chaperones, i.e. DNJ and ABX during coadministration with therapeutic GAA to stabilize GAA and prevent its degradation and hence increase the level of circulating GAA and that would provide increase in the uptake to different tissues including spinal cord as was discussed by Puzzo. Therefore, the synergistic effect of the combined administration of DNJ and ABX to enhance gene therapy efficacy, particularly in increasing the levels of GAA in spinal cord is expected.
Finally, the advantage of the combination of DNJ and ABX during GAA gene therapy recognized by the Applicant does not make the combination of prior art non-obvious because the prior art does not need to point out all advantages if there is a motivation to combine the prior art. MPEP 2145: “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.")”. In instant case, although Lukas does not directly teach effect of DNJ/ABX combination for in vivo increase in the uptake of therapeutic GAA into the spinal cord, Puzzo teaches uptake of therapeutic GAA into the spinal cord and discusses its dependence on high amount of GAA in circulation, DNJ is shown by Khanna to increase stability and circulation amount of GAA and ABX is shown by Lukas to synergistically increase DNJ action providing motivation for coadministration of DNJ/ABX combination during GAA gene therapy taught by Puzzo.
Therefore the 35 U.S.C. 103 rejection is maintained and modified necessitated by amendment of claims.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/L.G.K./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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