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
The instant application is a national stage entry under 35 USC 371 of PCT/US2021/045443 (filed on 8/10/2021), which claims priority to Provisional application 63/063,852 (filed on 8/10/2020).
Claims Status
A preliminary amendment was received 8/30/2023. Claims 1-12, 18-22, 24-27, 30-31, and 35 are pending, all of which have been considered on the merits.
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.
Claims 1-7,10-12,30-31,35 are rejected under 35 U.S.C. 103 as being unpatentable over Chen Plotkin et al (US 20190328906A1 as cited in the IDS), in view of McIvor et al. (WO 2016/187017A1) and in further view of Abeliovich et al (WO 2019/070894 A1 as cited in the IDS).
Chen Plotkin et al teach methods of treating diseases in mammals caused by a deficiency or defects in progranulin (GRN) activity or expression (See ¶0064). The method involves administering an rAAV particles that direct expression of a protein having GRN activity (rAAV-GRN particles) (See ¶0064). The rAAV-GRN particles can be delivered to the central nervous system, including the cerebral spinal fluid, brain ventricle, brain’s parenchyma, subarachnoid space or intrathecal space (See ¶0064-0068). The administration of the rAAV-GRN particles direct expression of the GRN protein in the mammal (See ¶0126). Chen Plotkin et al teaches an invention with a gene delivery system of rAAV comprised of a vector containing a nucleic acid (transgene) encoding progranulin (nucleic acid having SEQ ID NO: 2) (See, ¶ 0112).
The subjects to be treated include homozygous and heterozygous subjects such as humans with a GRN mutation that leads to deficiency (See ¶0063). The subject can be one with frontotemporal dementia (FTD) or Battens disease (See ¶0063).
Chen Plotkin et al teaches the method can further include administering or delivering one or more immuno-suppressive agents prior or contemporaneously with administration or delivery of rAAV vector (See ¶0113). The immunosuppressive agents can be an anti-inflammatory agent, cyclosporine, mycophenolate or a derivative thereof (See ¶0114-0115).
Chen Plotkin et al teaches the rAAV can have an AAV9 serotype, including an AAV9 capsid (See ¶0093-0094).
Chen Plotkin et al teaches the rAAV with AAV9 serotype can comprises one or two ITRs that correspond to native type inverted terminal repeats (ITRs) of AAV2 particles (See ¶0098). The ITRs can flank the polynucleotide that encodes PGN at the 5’ and 3’ respectively (See, ¶0080).
Chen Plotkin et al teaches the rAAV can include one or more expression control or regulatory elements operably linked to open reading frames of the transgene to direct transcription and translation of polypeptide encoded (See, ¶ 0154). The regulatory element includes initiation sequences such as promoters, enhancers, a TATA box and or polyA sequences (See, ¶ 0154). Chen Plotkin et al the rAAV-GRN particles can include an expression control element, which can be a promoter and or enhancer element; including CMV enhancer, chicken beta actin promoter and/or CAG promoter (See ¶0162).
Chen Plotkin et al teaches administering the rAAV-GRN particles at a dose of about 1 x 106 to about 1 x 1018 vg/kg (See ¶0130). The rAAV-GRN particles can be administered by intraventricular injection or intraparenchymal injection (See ¶0123-0127). Chen Plotkin et al teach single or multiple administrations (See ¶0129). Chen Plotkin et al also teaches that rAAV and or immunosuppressive agent can be formulated to be suitable for the particular route of administration (See, ¶0118).
Regarding claims 1 and 2, Chen Plotkin et al teaches a method of treating a subject having FTD with a GRN mutation comprising administrating (1) an rAAV comprising an rAAV9 vector containing a promoter operably linked to a nucleic acid encoding progranulin (a transgene encoding for PRGN), in combination with (2) immunosuppressive agents. The rAAV9 vector contains a AAV9 capsid protein. Administration of an immunosuppressive agent will necessarily also suppress an immune response in the FTD patient with the GRN mutation.
Chen Plotkin et al differs from the methods of claim 1 and 2 in that Chen Plotkin does not specifically teach the immunosuppression or immunotolerizing agents sirolimus and does not teach progranulin nucleic acid sequence of SEQ ID NO: 68 of the instant application.
Regarding the immunosuppressant agent: McIvor et al teaches a method to treat symptoms associated with disease of the central nervous system. The treatment includes administering a rAAV encoding a gene product associated with the disease in an effective amount (See, abstract). McIvor et al also teaches the treatment comprising of an effective amount of rAAV serotype 9 (rAAV9) vectors and the co-therapy to induce immunosuppression or immunotolerizing agent to achieve higher levels of expression (See, p 3 line 24-29 and line 38-40). The immunosuppressants can be a glucocorticoid, cytotoxic antibiotic, an antibody, and or sirolimus (See, p 5 line 9-17). McIvor teaches an embodiment where the rAAV and the immune suppressant or immunotolerizing agent are co-administered or the immune suppressant is administered after rAAV (See, p 5 line 17-18). McIvor teaches that immune suppressant or tolerizing agent may be administered subcutaneously, intramuscular, or intravenously injection, orally, intracranially or by sustained release (See, p 23 line 26-28).
McIvor et al discloses that the dosage of the immune suppressant or immunotolerizing agent is administered within a wide range and will depend on various factors such as severity of the disease, the age of the patient, and may be individually adjusted, such that possible range for the amount to be administered may be 0.1 mg to about 2000 mg or about 1 mg to about 2000 mg per day (See, p 24 line 14-18). It is also disclosed that the formulations can contain immune suppressants with one or more rAAV encoding a therapeutic gene product (See, p 24 line 20-21). McIvor et al teaches that dosage forms can be administered daily, or more than once a day or less frequently than daily, if found to be advisable by physician (See, p 26 line 25-27).
Given that both Chen Plotkin and McIvor teach immune suppressive agents that can be administered in conjunction with rAAV-based gene therapies for treating neurological diseases it would have been prima facie obvious to substitute one immune suppressing or tolerizing agent for the other. Specifically, it would have been prima facie obvious to have modified the method of Chen Plotkin to substitute the sirolimus of McIvor for the mycophenolate of Chen Plotkin et al. One would have had a reasonable expectation that the sirolimus of McIvor et al would serve as an effective immunosuppressant in place of the mycophenolate because they are both disclosed to be immunosuppressants. Substitution of one element for another in the field, wherein the results of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Regarding the sequence of the nucleic acid encoding PGRN: Abeliovich et al discloses a method to treat diseases associated with aberrant lysosomal function, like Parkinson's disease and Gaucher disease (See, abstract). Abeliovich et al teaches an embodiment comprising of isolated nucleic acid SEQ ID NO: 68, which is identical to SEQ ID NO: 68 of the instant application (See, sequence alignment at the end of action). Abeliovich et al also teaches SEQ ID NO 28, which is identical to SEQ ID NO: 28 of the instant application ( See sequence alignment at the end of the action).
Given that both Chen Plotkin and Abeliovich teach transgene/nucleic acid that can be utilized for gene therapy, it would have been prima facie obvious to have modified the method of Chen Plotkin to substitute the GRN (SEQ ID NO: 2), that encodes for wild type GRN, with the GRN (SEQ ID NO: 68) of Abeliovich et al, which encodes for a codon optimized GRN for humans. One would have had a reasonable expectation that the GRN (SEQ ID NO: 68) of Abeliovich would serve as an effective nucleic acid sequence for the method of Chen Plotkin et al because they are both disclosed to encode for GRN. Substitution of one element for another in the field, wherein the results of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Therefore, the methods of claims 1 and 2 are obvious over Chen Plotkin et al in view of McIvor et al and further view of Abeliovich et al.
Regarding claim 3 and 4, following the discussion of claim 1 above, Chen Plotkin et al teaches the administering of the rAAV at a dose of about 1 x 1013 to about 1 x 1015 vg/kg (See ¶0130-0131) by intraventricular injection and the claim limitation is administrating to the subject at a dose ranging from about 1 x 1013 vg to about 7 x 1014vg for claim 3 and the range from claim 4, dose about 3.5 x 1013vg, about 7.0 x 1013 vg or about 1.4 x 1014 vg. Chen Plotkin et al teaches that dosage of formulation can be modified for particular administration methods (See, ¶0118).
Therefore, Chen Plotkin et al provides explicit motivations to optimize the administered dosage to achieve desired outcomes in subjects, and illustrates that such optimization would have been a matter of routine experimentation. Thus, it would have been obvious to one of the skills in the art prior to the effective filing date to optimize the administered dosage to achieve outcomes in subjects.
In this case of a result effective variable, the discovery of an optimum value of the variable known in the art, where the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the optimum to one of the ordinary skills in the art to determine through routine experimentation the optimum workable ranges of parameters such as administered dosage since the variables would have been recognize as result-effective (See, MPEP 2144.05)
Therefore, the methods of claim 3 and 4 are obvious over Chen Plotkin et al in view of McIvor et al and further view of Abeliovich et al.
Regarding claim 5, following the discussion of claim 1 above, Chen Plotkin et al teaches administering the injection to the subarachnoid space, which includes the cisterna magna. This clearly reads on the limitation of claim 5, wherein the rAAV is administered via injection to the cisterna magna.
Therefore, the method of claim 5 is obvious over Chen Plotkin et al in view of McIvor et al and further view of Abeliovich et al..
Regarding claims 6-7, following the discussion of claim 1 above, Chen Plotkin et al teaches the rAAV includes an expression control element, which can be comprised of a promoter and or enhancer element; including CMV enhancer, chicken beta actin promoter and or CAG promoter (See, p 2 line 0017), which reads on promoter is a chicken beta actin (CBA) promotor of claim 6 and rAAV vector further comprises a cytomegalovirus (CMV) enhancer of claim 7.
Therefore, the methods of claims 6-7 are obvious over Chen Plotkin et al in view of McIvor et al and further view of Abeliovich et al.
Regarding claims 10-11, following the discussion of claim 1 above, Chen Plotkin et al teaches the use of an rAAV comprising of an AAV 9 capsid protein and the nucleic acid is inserted between a pair of AAV inverted terminal repeats (ITR) (See, ¶ 0014, ¶0092), such that one or more pairs of ITRs comprises of AAV2 (See, ¶ 0016). For the ITRs, it is taught that the pair of ITRs that flank the polynucleotide are 5’ and 3’ respectively (See, ¶ 0080). This teaching reads on the limitation of claim 10, comprises two AAV ITR sequences…, where in the first ITR sequence is a 5’ ITR and the second ITR sequence is a 3’ ITR. Limitation of claim 11, where in each of the two ITR sequences is an AAV 2 ITR sequence, is read on by the teaching of Chen Plotkin et al (See, ¶ 0016).
Therefore, the methods of claims 10-11 are obvious over Chen Plotkin et al in view of McIvor et al and further view of Abeliovich et al.
Regarding claim 12, following the discussion of claim 10 above, Chen Plotkin et al teaches the nucleic acids can include one or more expression control or regulatory elements operably linked to open reading frames to direct transcription and translation of polypeptide encoded (See, ¶ 0154). The regulatory element includes initiation sequences such as promoters, enhancers, a TATA box and or polyA sequences (See, ¶ 0154). This reads on a TRY region between the 5' ITR and the expression construct of claim 12.
Chen Plotkin et al does not teach SEQ ID NO: 28 of claim 12. Abeliovich et al teaches SEQ ID NO: 28, which is identical to SEQ ID NO: 28 of the instant application ( See, sequence alignment at the end of the action). Chen Plotkin et al teaches that dosage of formulation can be modified for particular administration methods (See, ¶0118).
Therefore, Chen Plotkin et al provides explicit motivations to optimize the regulatory elements in the formulation to achieve desired outcomes in subjects, and illustrates that such optimization would have been a matter of routine experimentation. Thus, it would have been obvious to one of the skills in the art prior to the effective filing date to optimize the administered dosage to achieve outcomes in subjects.
In this case of a result effective variable, the discovery of an optimum formulation of the variable known in the art, where the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the optimum to one of the ordinary skills in the art to determine through routine experimentation the optimum workable parameters such as nucleic acid sequence of the formulation of regulatory elements since the variables would have been recognize as result-effective (See, MPEP 2144.05)
Therefore, method of claim 12 is obvious over Chen Plotkin et al in view of McIvor et al and further view of Abeliovich et al.
Regarding claims 30-31 and 35, following the discussion of claim 2 above, Chen Plotkin et al teaches that use of immunosuppression and immunotolerizing agents to overcome and manage the immune response to the rAAV administration to improve efficacy (See, ¶ 0058). Therefore, it would be inherent that there is or can be an immune response from the rAAV. This reads on wherein in the immune response is an immune response to the rAAV limitation of claim 30 and wherein the immune response is a T cell response, a B cell response, an antibody response, pleocytosis, or an abnormal level of CSF protein of claim 31, and where the pleocytosis is CSF pleocytosis of claim 35. due to the nature of immune responses and the site of the administration of the method in Chen Plotkin et al and McIvor et al, it is inherent result of the method.
Therefore, claims 30-31 and 35 are obvious over Chen Plotkin et al in view of McIvor et al and in further view of Abeliovich et al.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Chen Plotkin et al., McIvor et al. and Abeliovich et al as applied to claims 1-7,10-12,30-31,35 above, and further in view of Choi et al. (Molecular brain, 2014).
Regarding claims 8-9, following the discussion of claim 1 above, Chen Plotkin et al teaches the rAAV includes an expression control element, which can be comprised of a promoter and or enhancer element; including CMV enhancer, chicken beta actin promoter and or CAG promoter (See, ¶0017).
Chen Plotkin et al differs from claims 8 and 9 in that Chen Plotkin does not teach the specific use of vectors comprising of WPRE or Bovine growth Hormone polyA signal tail.
Choi et al teaches AAV vectors that deliver transgenes to diverse cell types as gene therapy. Choi et al teaches generating a series of AAV expression cassettes comprising of woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) and bovine growth hormone polyadenylation signal (polyA signal) (See, p 2 col 1 or p 8 Methods).
Given that both Chen Plotkin and Choi teach AAV vectors that deliver transgenes as gene therapy, it would have been prima facie obvious to have substituted one for the other. Specifically, it would have been prima facie obvious to have modified the method of Chen Plotkin et al to substitute the expression control elements to WPRE or bovine growth hormone polyA signal of Choi et al for the expression control elements of Chen Plotkin et al. One would have had a reasonable expectation that the expression control elements of Choi et al would serve in the gene therapy because they are known elements used in the art and are shown to be effective. Substitution of one element for another known in the field, wherein the results of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Therefore, claims 8-9 are obvious over Chen Plotkin et al in view of McIvor et al and Abeliovich et al, and in further view of Choi et al.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Chen Plotkin et al., McIvor et al., and Abeliovich et al as applied to claims 1-7,10-12,30-31,35 above, and further in view of Patricio et al. (Molecular therapy. Methods and clinical development, 2019).
Regarding claim 18, following the discussion of claim 1 above, Chen Plotkin et al teaches a solution of suspension for the rAAV-GRN particles to contain sterile diluents for injection including, water, ethanol, polyol, nontoxic glyceryl esters and the inclusion of isotonic agents such as sugars, buffers, or salts (See, p9-10 lines 0136-0137).
Chen Plotkin et al differs from claim 18 in the specific formulation of the administered rAAV.
Patricio et al teaches the use of rAAV gene therapy for gene replacement. Patricio et al teaches that their viral stock is prepared in formulation buffer (TMN 200) containing 20mM Tris, pH 8.0, about 1mM MgCl2, about 200mM NaCl, and 0.001% PF68 (poloxamer 188) in water for injections (See, p 104 Methods).
Given that both Chen Plotkin and Patricio teach rAAV gene therapy and injectable rAAV for administration, it would be prima facie obvious to have modified the method of Chen Plotkin et al to substitute the sterile diluents for injection formulation with that of Patricio et al.
One would have had a reasonable expectation that the formulation of Patricio et al would serve in the gene therapy because they are known elements used in the art and are shown to be effective. Substitution of one element for another known in the field, wherein the results of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Therefore, claims 18 is obvious over Chen Plotkin et al, in view of McIvor et al and Abeliovich et al, and in further view of Patricio et al.
Claims 19-22 and 24-27 are rejected under 35 U.S.C. 103 as being unpatentable over Chen Plotkin et al in view of McIvor et al as applied to claim 1-7,10-12,30-31,35above, and further in view of Hareendran et al (Reviews in medical virology, 2013).
Regarding claims 19-22 and 24-27, follow the discussion of claim 1 above, Chen et al teaches a method that includes administering or delivering one or more immuno-suppressive agents prior or contemporaneously with administration or delivery of rAAV vector (See, ¶ 0058). The immunosuppressive agents can be an anti-inflammatory agent, cyclosporine, mycophenolate or a derivative thereof (See, ¶ 0058).
It is known within the field of the art that methylprednisolone and prednisone are glucocorticoids, which are immunosuppressive and anti-inflammatory agents; rituximab is a monoclonal antibody that targets B cells as an immunosuppressive agent; and sirolimus is an immunosuppressive that inhibits T and B cell proliferation. Yet, Chen Plotkin et al does not teach the use of the specific agents mentioned.
Hareendran et al teaches that to prevent unwarranted host immune responses to AAV-mediated gene therapy, a short-term suppression regiment induced during initial stages of vector administration is beneficial, as it creates a window period that improves the efficacy of the AAV gene therapy (See, p406 col 2). Hareendran et al teaches the administration of rituximab promoted tolerance (See, p406 col 2). It is also taught that there are multiple factors that can be optimized when it comes to AAV gene therapy, such as route of delivery and optimum dosage of AAV vector or immune suppression protocol (See, p409 col 2). Figure 6 of Hareendran et al teaches the various immune-suppressive agents utilized to modulate immune reactions, including corticosteroids, cyclosporine, and tacrolimus (See, p 407 col 1).
The use of corticosteroids (methylprednisolone or prednisone) and rituximab in place of cyclosporine and mycophenolate of Chen Plotkin et al, is predictable use of prior art elements according to their established functions, leading to the predictable results of immune suppressive agents modulating the immune response of administrating rAAV treatments.
This rationale aligns with the principle of KSR for a simple substitution of one known element for another to obtain predictable results, see MPEP 2143.
McIvor et al discloses that the dosage of the immune suppressant or immunotolerizing agent is administered within a wide range and will depend on various factors such as severity of the disease, the age of the patient, and may be individually adjusted, such that possible range for the amount to be administered may be 0.1 mg to about 2000 mg or about 1 mg to about 2000 mg per day (See, p 24 line 14-18). It is also disclosed that the formulations can contain immune suppressants with one or more rAAV encoding a therapeutic gene product (See, p 24 line 20-21). McIvor et al teaches that dosage forms can be administered daily, or more than once a day or less frequently than daily, if found to be advisable by physician (See, p 26 line 25-27). These teachings read on the limitations of claims 19-22 and 24-27 regarding the dosage and the timing of the dosages of the rAAV and or the immunosuppression or immunotolerizing agents and provides motivations to optimize the administration of immunosuppression and immunotolerizing agents and formulations with rAAV. Thus, it would have been obvious to one of skill in the art prior to the effective to optimize the dosage and timing of the administration of methylprednisolone, prednisone, rituximab, and sirolimus.
In this case of a result effective variable, the discovery of an optimum value of the variable in a known proves is ordinarily within the skill of the art. Where the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore, it would have been obvious to one of the ordinary skills in the art to determine through routine experimentation the optimum or workable ranges of parameters such as increasing or decreasing the dosage of immunosuppressive agents or the timing of the dosage in relation to each other or rAAV administration, since the variables would have been recognized as result-effective (See, MPEP 2144.05).
Therefore, claims 19-22 and 24-27 would be obvious over Chen Plotkin et al in view of McIvor et al and Abeliovich et al, and in further view of Hareendran et al.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Caroline M Lara whose telephone number is (571)272-4262. The examiner can normally be reached 7:00 to 3:00pm M-F.
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
SEQUENCE ALIGNMENTS
RE: WO 2019/070894 A1
Query (instant SEQ ID NO: 68) vs Subject (referenced SEQ ID NO:68)
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662
837
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Query instant SEQ ID NO: 28) vs Subject (referenced SEQ ID NO:28)
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458
759
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