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 .
Withdrawn Rejections
The rejection of claims 58, 60-61, 64-65, 71, and 77, under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, is withdrawn. Applicant’s amendments to the claims and arguments are persuasive in overcoming the rejection.
The rejection of claims 57-76, under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, is withdrawn. The amendment to the claims overcome this rejection.
The rejection of claim 76, under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn. The amendments to the claim overcome the rejection.
The rejection of claims 59 and 70, under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, is withdrawn. The amendments to the claims overcome this rejection.
The rejection of claims 66-76, under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement, in withdrawn. Applicant’s argument regarding the claims only requires increasing FXN levels in a subject, not a therapeutic effect and further amending the claims to include the UTR sequence that improve transgene expression is found persuasive. As such, the enablement rejection is withdrawn.
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.
(1) Claims 57-59, 62-64 and 65, as amended or previously presented,, are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 9 of U.S. Patent No. 11,116,852 alternatively said U.S. Patent No. in view of Mingozzi (US 2014/0336245)
Regarding claims 57-58, patent claim 9 teaches an AAV vector comprising a polynucleotide comprising a nucleic acid molecule encoding a human frataxin polypeptide having an amino acid sequence of SEQ ID NO:1, wherein the nucleic acid molecule is operably linked to a 5′UTR and a 3′UTR, wherein: the 5′UTR is RPL6-5′Splice and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7; or the 5′UTR is 5U2 and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7, wherein the encoded human frataxin polypeptide is a functional frataxin protein. Thus that patent discloses a species of the recombinant AAV of (i) in operable linkage to a control element as claimed in the instant claims. The patent claim does not expressly teach the empty capsids of (ii). However, (ii) in part recites “empty capsids at a percentage of about 0% cp/cp to about 25% cp/cp”. As such, the breadth of (ii) encompasses in one embodiment no inclusion of the empty capsids. This embodiment (i.e. 0% cp/cp) of the instant claims are taught by the teachings of claim 9 as discussed above. The patent claims do not teach that the AAV vector is part of a pharmaceutical composition as the preamble recites in the instant claim. However, pharmaceutical composition can be considered an intended use for the instant claims because the instant claims do not recite any specific structural pharmaceutical or drug related limitations that would limit the composition. As such, pharmaceutical composition, given its BRI, is not further limiting to the instant claims. Similarly, no particular “therapeutic amount” has been delineated by the claims. As such, it can be interpreted as any amount. Thus patent claim 1 is an obvious species of instant claim 57.
Even further, to address the empty capsid limitation above 0% cp/cp, Mingozzi (US 2014/0336245) teaches methods of increasing or improving gene transduction by way of gene therapy to a patient are provided by employing a viral vector formulation. In one embodiment, a method includes administering a viral vector comprising a transgene to a cell; and administering empty capsids, viral genome-containing capsids, or viral capsid proteins to the subject in an amount effective to increase or improve transduction of a transgene into the cell. In another embodiment, a method includes administration of a predetermined ratio of viral vectors and administration of empty capsids, wherein the viral vector includes a transgene and the predetermined amount of empty capsids is calculated to inhibit undesired immune responses to said formulation in said patient. In a further embodiment, a method includes administration of a predetermined ratio of viral vectors and viral genome containing capsids wherein the viral vector includes a transgene and the predetermined amount of viral genome containing capsids is calculated to inhibit undesired immune responses to said formulation in said patient. In still another embodiment, a method includes administration of a predetermined ratio of viral vectors and capsid proteins wherein the viral vector includes a transgene and the predetermined amount of capsid proteins is calculated to inhibit undesired immune responses to said formulation in said patient ([0010]). In particular embodiments of invention formulations, compositions, methods and uses disclosed herein, the viral vectors and capsids (empty or genome containing) or capsid proteins are adeno-associated virus (AAV) vectors or AAV capsids. Such AAV vectors, capsids (empty or genome containing) or capsid proteins can be identical or different serotypes, and can be any naturally and non-naturally occurring AAV serotypes. Such non-limiting serotypes include, for example, AAV-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -rh74, -rh10 and AAV-2i8 ([0013]). In additional aspects, the vectors and capsids (empty or genome containing) or capsid proteins are present in a biologically acceptable carrier suitable for administration. In various aspects, systemic, regional or local administration of the formulation is employed. Also provided is a method for delivering a transgene to a cell which comprises administration of an effective amount of the formulation to a patient in need thereof. In one embodiment, the patient has a metabolic or genetic disorder and the transgene encodes a therapeutic molecule which corrects or ameliorates one or more symptoms of the disorder ([0015]-[0016]).
As such, it would have been obvious to an artisan of ordinary skill at the time of the invention to include a therapeutically effective percentage of empty AAV capsids as taught by Mingozzi in a composition with the AAV vector of patent claim 9 to predictably arrive at the limitations of instant claims 57 and 58. As artisan would have a reasonable expectation of success because Mingozzi teaches that a therapeutically effective amount of empty capsid can be determined to arrive at the claimed composition to effectively neutralize immune responses. Mingozzi also provides a motivation to do so in the ability of empty capsids to improve transduction by neutralizing immune responses to the AAV vector of patent claim 9. Thus, patent claim 9 in view of Mingozzi is an obvious variant of instant claims 57-58.
Regarding claim 59, this claim specify that SEQ ID NO:1 differs from SEQ ID NO:2. This claim does not impart any structural distinction to SEQ ID NO:1 as claimed or to any of the other structures of claim 59. As such, this claim does not further limit its base claim. Thus, patent claim 9 in view of Mingozzi renders instant claim 59 obvious for reasons discussed above.
Regarding claims 62-64, patent claim 9 does not discloses operable linkage to a constitutive or tissue specific promoter. However, Mingozzi teaches that the expression vector of their invention comprise tissue/cell specific promoter, inducible promoter, or ubiquitous promoters, including muscle specific promoters and PGK promoters ([0062]-[0070]). Thus at the time of the invention, the claimed promoters well established and commonly uses in gene therapy vectors such as that described in Testi.
Regarding claim 65, patent claim 9 in view of Mingozzi does not teach the claimed AAV concentration. However, MPEP § 2144.05 (II) states the following:
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. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In reHoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc.v.Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In reKulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
A review of the specification fails to provide evidence that the claimed concentration are critical. Absent such evidence it would have been obvious to an artisan of ordinary skill at the time of effectively filing the patent to try a finite number of possible concentration of the precursor component to predictably arrive at the claimed concentration through routine optimization. An artisan would have a reasonable expectation of success in optimizing the concentrations because determine method of determining therapeutic AAV concentration were established in the art. Thus patent claim 9 in view of Mingozzi renders the instantly claimed concentration above.
(2) Claim 77, as amended, is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20 and 23 of U.S. Patent No. 11,116,852.
Patent claim 20 teaches a composition comprising: (a) a viral vector, wherein said vector comprises a nucleic acid molecule encoding human frataxin operably linked to a 5′UTR, a 3′UTR, and a control element that directs transcription and/or translation, wherein: the 5′UTR is RPL6-5′Splice and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7; or the 5′UTR is 5U2 and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7; and (b) a pharmaceutically acceptable excipient, wherein said nucleic acid encodes a protein with the amino acid sequence of SEQ ID NO:1, the control element is a UBC promoter, the 5′UTR is 5U2, and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7, wherein said nucleic acid encodes a protein with the amino acid sequence of SEQ ID NO:1, the control element is a UBC promoter, the 5′UTR is 5U2, and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7. Alternatively patent claim 22 teaches a composition comprising: (a) a viral vector, wherein said vector comprises a nucleic acid molecule encoding human frataxin operably linked to a 5′UTR, a 3′UTR, and a control element that directs transcription and/or translation, wherein: the 5′UTR is RPL6-5′Splice and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7; or the 5′UTR is 5U2 and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7; and (b) a pharmaceutically acceptable excipient, wherein said nucleic acid encodes a protein with the amino acid sequence of SEQ ID NO:1, the control element is a UBC promoter, the 5′UTR is 5U2, and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7, wherein said nucleic acid encodes a protein with the amino acid sequence of SEQ ID NO:1, the control element is a UBC promoter, the 5′UTR is RPL6-5′ Splice, and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7. Thus both patent claims 20 and 23 teach the limitations of the viral vector of (a) and (b) the pharmaceutically acceptable excipient.
The patent claims do not teach the claimed AAV concentration. However, MPEP § 2144.05 (II) states the following:
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. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In reHoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc.v.Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In reKulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
A review of the specification fails to provide evidence that the claimed concentration are critical. Absent such evidence it would have been obvious to an artisan of ordinary skill at the time of effectively filing the patent to try a finite number of possible concentration of the precursor component to predictably arrive at the claimed concentration through routine optimization. An artisan would have a reasonable expectation of success in optimizing the concentrations because determine method of determining therapeutic AAV concentration were established in the art. Thus patent claim 20 and alternatively patent claim 23, renders the instantly claimed concentration above obvious.
Patent claims 20 and 23 do not teach wherein the pH of the pharmaceutical formulation is about 6.5 to about 7.5. However, determining the optimal pH for a pharmaceutical composition was well established by the time of the patent claims. Thus it would be obvious before the time of effectively filing of the patent claims to optimize their pH to predictably arrive at the limitations of instant claim 77. As such patent claim 20 and 23 are obvious variants of instant claim 77.
(3) Claims 66-70 and 73-76, as amended or previously presented, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 19 of U.S. Patent No. 11,998,618 in view of Mingozzi (US 2014/0336245).
Regarding instant claim 66, patent claim 19 teaches a method of increasing frataxin levels in a subject having a frataxin deficiency, the method comprising administering to the subject: an adeno-associated viral (AAV) vector, wherein said AAV vector comprises a nucleic acid molecule encoding human frataxin operably linked to: a 5′UTR selected from 5U2, FTH1, GAPDH, and RPL6-5′Splice; a 3′UTR selected from a SV40 early adenylation sequence, a SV40 late adenylation sequence, a human growth hormone polyadenylation sequence (hGHpA), and a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7; and a control element that directs transcription and/or translation, wherein the frataxin encoded by the nucleic acid molecule is produced by the subject at a level that is at least 25% of frataxin levels produced by a subject not having a frataxin deficiency, wherein the administering comprises intrathecal (IT) administration, intracerebroventricular (ICV) administration, intraparenchymal administration, intracerebellar administration, or a combination thereof. Patent claim 19 does not teach the species of SEQ ID NO:1, or a fragment thereof. However, SEQ ID NO:1 is the full human wild-type sequence for FXN. As such, an artisan of ordinary skill before the time of the patent claim would preferentially choose the wild-type full sequence of human FXN of SEQ ID NO:1 to combine with the patent claim to predictably arrive at the limitations of instant claim 66 with a reasonable expectation of success because SEQ ID NO:1 was a prior art established human FXN sequence.
The patent claim does not expressly teach the empty capsids of (ii). However, (ii) in part recites “empty capsids at a percentage of about 0% cp/cp to about 25% cp/cp”. As such, the breadth of (ii) encompasses in one embodiment no inclusion of the empty capsids. This embodiment (i.e. 0% cp/cp) of the instant claims are taught by the teachings of claim 19 as discussed above. The patent claims do not teach that the AAV vector is part of a pharmaceutical composition as the preamble recites in the instant claim. However, pharmaceutical composition can be considered an intended use for the instant claims because the instant claims do not recite any specific structural pharmaceutical or drug related limitations that would limit the composition. As such, pharmaceutical composition, given its BRI, is not further limiting to the instant claims. Similarly, no particular “therapeutic amount” has been delineated by the claims. As such, it can be interpreted as any amount. Thus patent claim 19 is an obvious species of instant claim 66.
Even further, to address the empty capsid limitation above 0% cp/cp, Mingozzi (US 2014/0336245) teaches methods of increasing or improving gene transduction by way of gene therapy to a patient are provided by employing a viral vector formulation. In one embodiment, a method includes administering a viral vector comprising a transgene to a cell; and administering empty capsids, viral genome-containing capsids, or viral capsid proteins to the subject in an amount effective to increase or improve transduction of a transgene into the cell. In another embodiment, a method includes administration of a predetermined ratio of viral vectors and administration of empty capsids, wherein the viral vector includes a transgene and the predetermined amount of empty capsids is calculated to inhibit undesired immune responses to said formulation in said patient. In a further embodiment, a method includes administration of a predetermined ratio of viral vectors and viral genome containing capsids wherein the viral vector includes a transgene and the predetermined amount of viral genome containing capsids is calculated to inhibit undesired immune responses to said formulation in said patient. In still another embodiment, a method includes administration of a predetermined ratio of viral vectors and capsid proteins wherein the viral vector includes a transgene and the predetermined amount of capsid proteins is calculated to inhibit undesired immune responses to said formulation in said patient ([0010]). In particular embodiments of invention formulations, compositions, methods and uses disclosed herein, the viral vectors and capsids (empty or genome containing) or capsid proteins are adeno-associated virus (AAV) vectors or AAV capsids. Such AAV vectors, capsids (empty or genome containing) or capsid proteins can be identical or different serotypes, and can be any naturally and non-naturally occurring AAV serotypes. Such non-limiting serotypes include, for example, AAV-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -rh74, -rh10 and AAV-2i8 ([0013]). In additional aspects, the vectors and capsids (empty or genome containing) or capsid proteins are present in a biologically acceptable carrier suitable for administration. In various aspects, systemic, regional or local administration of the formulation is employed. Also provided is a method for delivering a transgene to a cell which comprises administration of an effective amount of the formulation to a patient in need thereof. In one embodiment, the patient has a metabolic or genetic disorder and the transgene encodes a therapeutic molecule which corrects or ameliorates one or more symptoms of the disorder ([0015]-[0016]).
As such, it would have been obvious to an artisan of ordinary skill at the time of the invention to include a therapeutically effective percentage of empty AAV capsids as taught by Mingozzi in a composition with the AAV vector of patent claim 19 to predictably arrive at the limitations of instant claim 66. As artisan would have a reasonable expectation of success because Mingozzi teaches that a therapeutically effective amount of empty capsid can be determined to arrive at the claimed composition to effectively neutralize immune responses. Mingozzi also provides a motivation to do so in the ability of empty capsids to improve transduction by neutralizing immune responses to the AAV vector of patent claim 19. Thus, patent claim 19 in view of Mingozzi is an obvious variant of instant claim 66.
Regarding claim 67, patent claim 1 teaches A method of treating at least one symptom of Friedreich's Ataxia (FA) in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a composition comprising: (a) an adeno-associated viral (AAV) vector, wherein said AAV vector comprises a nucleic acid molecule encoding human frataxin operably linked to: a 5′UTR selected from 5U2, FTH1, GAPDH, and RPL6-5′Splice; a 3′UTR selected from a SV40 early adenylation sequence, a SV40 late adenylation sequence, a human growth hormone polyadenylation sequence (hGHpA), and a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7; and a control element that directs transcription and/or translation; and (b) a pharmaceutically acceptable excipient, wherein the at least one symptom of Friedreich's Ataxia comprises loss of coordination in the arms and/or legs; and wherein the administering comprises intrathecal (IT) administration, intracerebroventricular (ICV) administration, intraparenchymal administration, intracerebellar administration, or a combination thereof.
Patent claim 1 does not teach the species of SEQ ID NO:1, or a fragment thereof. However, SEQ ID NO:1 is the full human wild-type sequence for FXN. As such, an artisan of ordinary skill before the time of the patent claim would preferentially choose the wild-type full sequence of human FXN of SEQ ID NO:1 to combine with the patent claim to predictably arrive at the limitations of instant claim 67 with a reasonable expectation of success because SEQ ID NO:1 was a prior art established human FXN sequence.
The patent claim does not expressly teach the empty capsids of (ii). However, (ii) in part recites “empty capsids at a percentage of about 0% cp/cp to about 25% cp/cp”. As such, the breadth of (ii) encompasses in one embodiment no inclusion of the empty capsids. This embodiment (i.e. 0% cp/cp) of the instant claims are taught by the teachings of claim 1 as discussed above. The patent claims do not teach that the AAV vector is part of a pharmaceutical composition as the preamble recites in the instant claim. However, pharmaceutical composition can be considered an intended use for the instant claims because the instant claims do not recite any specific structural pharmaceutical or drug related limitations that would limit the composition. As such, pharmaceutical composition, given its BRI, is not further limiting to the instant claims. Similarly, no particular “therapeutic amount” has been delineated by the claims. As such, it can be interpreted as any amount. Thus patent claim 1 is an obvious species of instant claim 67.
Even further, to address the empty capsid limitation above 0% cp/cp, Mingozzi (US 2014/0336245) teaches methods of increasing or improving gene transduction by way of gene therapy to a patient are provided by employing a viral vector formulation. In one embodiment, a method includes administering a viral vector comprising a transgene to a cell; and administering empty capsids, viral genome-containing capsids, or viral capsid proteins to the subject in an amount effective to increase or improve transduction of a transgene into the cell. In another embodiment, a method includes administration of a predetermined ratio of viral vectors and administration of empty capsids, wherein the viral vector includes a transgene and the predetermined amount of empty capsids is calculated to inhibit undesired immune responses to said formulation in said patient. In a further embodiment, a method includes administration of a predetermined ratio of viral vectors and viral genome containing capsids wherein the viral vector includes a transgene and the predetermined amount of viral genome containing capsids is calculated to inhibit undesired immune responses to said formulation in said patient. In still another embodiment, a method includes administration of a predetermined ratio of viral vectors and capsid proteins wherein the viral vector includes a transgene and the predetermined amount of capsid proteins is calculated to inhibit undesired immune responses to said formulation in said patient ([0010]). In particular embodiments of invention formulations, compositions, methods and uses disclosed herein, the viral vectors and capsids (empty or genome containing) or capsid proteins are adeno-associated virus (AAV) vectors or AAV capsids. Such AAV vectors, capsids (empty or genome containing) or capsid proteins can be identical or different serotypes, and can be any naturally and non-naturally occurring AAV serotypes. Such non-limiting serotypes include, for example, AAV-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -rh74, -rh10 and AAV-2i8 ([0013]). In additional aspects, the vectors and capsids (empty or genome containing) or capsid proteins are present in a biologically acceptable carrier suitable for administration. In various aspects, systemic, regional or local administration of the formulation is employed. Also provided is a method for delivering a transgene to a cell which comprises administration of an effective amount of the formulation to a patient in need thereof. In one embodiment, the patient has a metabolic or genetic disorder and the transgene encodes a therapeutic molecule which corrects or ameliorates one or more symptoms of the disorder ([0015]-[0016]).
As such, it would have been obvious to an artisan of ordinary skill at the time of the invention to include a therapeutically effective percentage of empty AAV capsids as taught by Mingozzi in a composition with the AAV vector of patent claim 1 to predictably arrive at the limitations of instant claim 67. As artisan would have a reasonable expectation of success because Mingozzi teaches that a therapeutically effective amount of empty capsid can be determined to arrive at the claimed composition to effectively neutralize immune responses. Mingozzi also provides a motivation to do so in the ability of empty capsids to improve transduction by neutralizing immune responses to the AAV vector of patent claim 1. Thus, patent claim 1 in view of Mingozzi is an obvious variant of instant claim 67.
Regarding claims 68-69, patent claim 1 and 19 teach the routes of administration as discussed above. As such, for reasons discussed above, patent claims 1 and 19 in view of Mingozzi render claims 68-69 obvious.
Regarding claim 70, this claim specify that SEQ ID NO:1 differs from SEQ ID NO:2. This claim does not impart any structural distinction to SEQ ID NO:1 as claimed or to any of the other structures of claim 70. As such, this claim does not further limit its base claim. Thus, patent claims 1 and 19 in view of Mingozzi renders instant claim 70 obvious for reasons discussed above.
Regarding claim 73, patent claim 1 does not teach the subject having the age of about 18 to about 60, or a child less than 3, 10 or 17 years old. However, before the time of effectively filing the patent, the above ages of the subject for developing FA were well established in the prior art. As such, it would have been obvious to apply the method of patent claim 1 to any of these subject because they were the known population impacted by FA. As such, patent claim 1 in view of Mingozzi renders instant claim 73 obvious.
Regarding claims 74-75, patent claim 1 teaches the limitations of increasing in FXN levels improves at least one symptom caused by a deficiency in FXN, more particularly a loss of coordination in limbs (motor skill). Thus patent claim 1 in view of Mingozzi renders the limitations of claims 74-75 obvious for reasons discussed above.
Regarding claim 76, patent claim 1 does not teach the increase in baseline test parameters of the claim. However, all of the claimed measure are known measures for assessing Friedreich’s Ataxia. Thu sis would have been obvious to artisan of ordinary skill to assess the improvement by the recited test of claim 76 in the method of patent claim 1 with a reasonable expectation of successfully arriving at the limitations of claim 76. As such, patent claim 76 is an obvious variant of patent claim 1 in view of Mingozzi.
(4) Claims 57-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26 and 56 of copending Application No. 17/326,884 in view of Mingozzi. The rational for the rejection is the same as discussed above.
This is a provisional nonstatutory double patenting rejection.
Response to Applicant’s Remarks-Double Patenting
Applicant request that the double patenting rejections be held in abeyance until the claims are otherwise found allowable. In response, the double patenting rejections are maintained.
Claim Rejections - 35 USC § 103
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.
Claim(s) 57-59 and 62-65, as amended or previously presented, is/are rejected under 35 U.S.C. 103 as being unpatentable over Testi (US 9,217,019 effectively filed:7/28/2010) in view of Mingozzi (US 2014/0336245).
Regarding claim 57, Testi teaches a human FXN nucleic acid sequence for use in a pharmaceutical composition to treat FRDA and introduce into cells (Figure 2; abstract). Testi teach that the FXN nucleic acid can be incorporated into a viral vector system, including AAV viral vectors for FXN gene deficiency treatment (col 13, line 62, to col 14, line 44). The sequence of figure 2 discloses a sequence encoding FXN of SEQ ID NO:1 or a fragment thereof.
Testi does not expressly teach the empty capsids of (ii). However, (ii) in part recites “empty capsids at a percentage of about 0% cp/cp to about 25% cp/cp”. As such, the breadth of (ii) encompasses in one embodiment no inclusion of the empty capsids. This embodiment (i.e. 0% cp/cp) of the instant claim is taught by the teachings Testi because it does not require the empty capsids.
To address the empty capsid limitation above 0% cp/cp, Mingozzi teaches methods of increasing or improving gene transduction by way of gene therapy to a patient are provided by employing a viral vector formulation. In one embodiment, a method includes administering a viral vector comprising a transgene to a cell; and administering empty capsids, viral genome-containing capsids, or viral capsid proteins to the subject in an amount effective to increase or improve transduction of a transgene into the cell. In another embodiment, a method includes administration of a predetermined ratio of viral vectors and administration of empty capsids, wherein the viral vector includes a transgene and the predetermined amount of empty capsids is calculated to inhibit undesired immune responses to said formulation in said patient. In a further embodiment, a method includes administration of a predetermined ratio of viral vectors and viral genome containing capsids wherein the viral vector includes a transgene and the predetermined amount of viral genome containing capsids is calculated to inhibit undesired immune responses to said formulation in said patient. In still another embodiment, a method includes administration of a predetermined ratio of viral vectors and capsid proteins wherein the viral vector includes a transgene and the predetermined amount of capsid proteins is calculated to inhibit undesired immune responses to said formulation in said patient ([0010]). In particular embodiments of invention formulations, compositions, methods and uses disclosed herein, the viral vectors and capsids (empty or genome containing) or capsid proteins are adeno-associated virus (AAV) vectors or AAV capsids. Such AAV vectors, capsids (empty or genome containing) or capsid proteins can be identical or different serotypes, and can be any naturally and non-naturally occurring AAV serotypes. Such non-limiting serotypes include, for example, AAV-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -rh74, -rh10 and AAV-2i8 ([0013]). In additional aspects, the vectors and capsids (empty or genome containing) or capsid proteins are present in a biologically acceptable carrier suitable for administration. In various aspects, systemic, regional or local administration of the formulation is employed. Also provided is a method for delivering a transgene to a cell which comprises administration of an effective amount of the formulation to a patient in need thereof. In one embodiment, the patient has a metabolic or genetic disorder and the transgene encodes a therapeutic molecule which corrects or ameliorates one or more symptoms of the disorder ([0015]-[0016]).
As such, it would have been obvious to an artisan of ordinary skill at the time of the invention to include a therapeutically effective percentage of empty AAV capsids as taught by Mingozzi in a composition with the AAV vector Testi to predictably arrive at the limitations of instant claim 57. As artisan would have a reasonable expectation of success because Mingozzi teaches that a therapeutically effective amount of empty capsid can be determined to arrive at the claimed composition to effectively neutralize immune responses. Mingozzi also provides a motivation to do so in the ability of empty capsids to improve transduction by neutralizing immune responses to the AAV vector of Testi. Thus, Testi in view of Mingozzi is an obvious variant of instant claim 57.
Regarding claim 58, Testi does not teach empty capsids at a percentage of about 50% to about 75% cp/cp. However, for the rationale discussed above Testi in view of Mingozzi teach these limitations and render then obvious.
Regarding clam 59, Testi in view of Mingozzi render obvious this claim because this claim does not further limit its base claim as discussed above.
Regarding claims 62-64, Testi is silent as to whether the promoters of their constructs are constitutive or tissue-specific promoters. However, Mingozzi teaches that the expression vector of their invention comprise tissue/cell specific promoter, inducible promoter, or ubiquitous promoters, including muscle specific promoters and PGK promoters ([0062]-[0070]). Thus at the time of the invention, the claimed promoters well established and commonly uses in gene therapy vectors such as that described in Testi.
As such, it would have been obvious before the time of effectively filing to use one of the commonly known predictable promoter taught by Mingozzi in the AAV vector of Testi to predictably arrive at the limitations of claims 62-64 with a reasonable expectation of success.
Regarding claim 65, Testi in view of Mingozzi does not teach the claimed concentration. However, MPEP § 2144.05 (II) states the following:
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. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In reHoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc.v.Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In reKulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
A review of the specification fails to provide evidence that the claimed concentration are critical. Absent such evidence it would have been obvious to an artisan of ordinary skill at the time of effectively filing the patent to try a finite number of possible concentration of the precursor component to predictably arrive at the claimed concentration through routine optimization. An artisan would have a reasonable expectation of success in optimizing the concentrations because determine method of determining therapeutic AAV concentration were established in the art. Thus Testi in view of Mingozzi renders the instantly claimed concentration above obvious.
(2) Claim 77, as amended, is/are rejected under 35 U.S.C. 103 as being obvious over Testi (US 9,217,019 effectively filed:7/28/2010) in view further of Reoth (US 9,402,919). Both references of record in IDS 7/24/2023.
Testi discloses a human FXN nucleic acid sequence for use in a pharmaceutical composition to treat FRDA and introduce into cells (Figure 2; abstract). Testi teach that the FXN nucleic acid can be incorporated into a viral vector system, including AAV viral vectors for FXN gene deficiency treatment (col 13, line 62, to col 14, line 44).
Testi does not teach that the nucleic acid molecule encoding frataxin is operably linked to a 5’UTR, wherein the 5’'UTR is 5U2, FTH1, GAPDH, or RPL6-5’Splice. However, Roeth teaches that their the invention comprises a vector conditionally expressing a protein wherein said vector comprises 5' UTR of 5U2, a codon-optimized nucleic acid sequence encoding IL-2 signal peptide, a codon-optimized coding region encoding a protein and a polyadenylation signal of SV40e or human growth hormone. Roeth teaches that the signal peptide and/regulatory region alone or in combination significantly increase productivity of the protein (col 66, lines 16-40). Roeth teaches that a great variety of expression vectors can be used to express proteins or polynucleotides. Suitable viral vectors include AAV based vectors (col 66, lines 48-67).
Therefore, at the time of effectively filing, it would have been obvious to an artisan of ordinary skill to introduce into the human frataxin nucleic acid molecule viral vector, preferably AAV vector, for expressing a protein, as taught by Testi that comprises the 5’UTR of 5U2 and a 3’ UTR with an SV40 polyA or hGHpA, taught by Roeth to predictably arrive at the limitations of claim 77. The artisan would have a reasonable expectation of success because recombinant molecular biology method to introduce said frataxin nucleic acid molecule into the AAV vector of Roeth were long established in the prior art. Further, the artisan would have been motivated to introduce the frataxin nucleic acid molecule, taught by Testi, into the AAV vector of Roeth comprising the 5’UTR of 5U2 and a 3’ UTR polA because Roeth teaches that this regulatory element alone or in combination with the signaling peptide significantly increases production of the transgene product protein. Thus, Testi in view of Roeth renders claim 77 obvious.
Testi in view of Roeth do not teach the claimed concentration for the viral vector. However, However, MPEP § 2144.05 (II) states the following:
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. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In reHoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc.v.Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In reKulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involv