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 .
This action is in response to the papers filed 11/19/2025.
Claims 1, 3, 6-8, 11, 15-16, 20, 26, 29, 35-36, 42, 44, 46-47, 52, 57, 64, 72 and 76-77 are pending in the application as set forth in the claim set filed 11/19/2025.
Therefore, claims 1, 3, 6-8, 11, 15-16, 20, 26, 29, 35-36, 42, 44, 46-47, 52, 57, 64, 72 and 76-77 are examined on the merits. Claims 1, 64, 72, and 76 are independent claims.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2023/016270 filed March 24, 2023.
Applicant’s claim for the benefit of a prior-filed parent provisional applications 63/438,164 filed 01/10/2023, 63/393,196 filed 07/28/2022, 63/341,841 filed 05/13/2022, 63/326,236 filed 03/31/2022, and 63/323,830 filed 03/25/2022 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is March 25, 2022.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 46 is rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
Claim 46 recites wherein the nucleic acid sequence has at least 85% sequence identity to the SEQ ID NO: 1.
As seen below, per SEQ ID NO:1 rge. search result, a nucleotide sequence that is 100% identical to SEQ ID NO:1 is known in the art with at least 20 duplicate listings for glial cell derived neurotropic factor (GDNF).
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Claim 46 recites at least 85% identity to SEQ ID NO:1 which is a sequence 636 nucleotides long.
Thus, the claims reasonably encompass as many as 95 nucleic acid substitutions, insertions, or deletions.
(4)95 = is about 1.5x1057 possible variants of SEQ ID NO:1 having at least 85% sequence identity to SEQ ID NO: 1.
However, the specification only discloses SEQ ID NO:1 and SEQ ID NOs 62 and 63 which are variants of the same length with a single substitution of C277T and C633G respectively.
Thus, it is immediately apparent to the ordinary artisan that the instant claims are vastly broader in scope to Applicant’s actual invention, an AAV2 vector comprising SEQ ID NO: 1, for encompassing an enormously vast genus of about 1.5x1057 structurally and functionally undisclosed variants of SEQ ID NO:1 that are to have the functional property of expressing GDNF in a subject affected by Parkinson’s disease.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Applicant’s specification fails to disclose a reduction to practice modifying and/or deleting 5, 10, 15, 20, 25, 30 (~95% identity), 60 (~90% identity) or as many as 95 nucleotides (85% identity) of SEQ ID NO:1, thereby generating an enormously vast genus of about 1.5x1057 variants of SEQ ID NO:1 that are to have the functional property of driving expression of an exogenous GDNF gene in a subject in need of treatment.
The claims fail to recite, and the specification fails to disclose, the structure/function nexus of the enormously vast genus of about 1.5x1057 variants of SEQ ID NO:1 that are to have the functional property of driving expression of an exogenous gene in a retinal ganglion cell and how to transform or otherwise modify a first variant to a functional equivalent.
Rather, Applicant’s working example(s) are directed to the use of a nucleotide sequence that is 100% identical to SEQ ID NO:1 within SEQ ID NO: 64 which is AAV2-GDNF.
The gap between the enormously vast genus of about 1.5x1057 structurally and functionally undisclosed, yet to be discovered, claimed variants of SEQ ID NO:1 is considered to be tremendous, notoriously difficult, slow, very laborious and time-consuming for the ordinary artisans to determine for themselves that which Applicant has failed to disclose.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claims 1, 3, 6-8, 11, 15-16, 20, 26, 29, 35-36, 42, 44, 46-47, 52, 57, 64, 72, 76 and 77 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for
a method of inhibiting or slowing the progression of Parkinson’s disease in a subject in need thereof comprising administering via infusion with intraoperative magnetic resonance image MRI -guided enhanced convection enhanced delivery (CED) into the putamen an rAAV composition comprising an AAV2 capsid, GDNF transgene operably linked to a CMV promoter, nervous system, or central nervous system promoter, wherein the rAAV is at a concentration of 3.3 x 1012 vg/mL, which achieves up to about 60% coverage of the putamen,
does not reasonably provide enablement for
a method of inhibiting or slowing the progression of Parkinson’s disease (PD) comprising introducing by any route of administration a rAAV composition comprising a rAAV comprising GDNF with any AAV capsid and any promoter at any dosage to achieve at least 30% coverage of the putamen.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The Breadth of the Claims and The Nature of the Invention
The claims are directed to a method of inhibiting or slowing the progression of Parkinson’s disease (PD) comprising introducing by any route of administration a rAAV composition comprising a rAAV comprising GDNF with any AAV capsid and any promoter at any dosage or concentration, thereby covering over 30% of the volume of the subject’s putamen and reducing or stabilizing PD-associated symptoms for at least 6 months.
The specification only discloses systemic and local introduction via the putamen (0009-0011).
The claims are broad for reasonably encompassing a multitude of anatomically and physiologically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, dermally, etc.
The specification discloses the rAAV is AAV1, AAV2, AAV3, AAV3b, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV 10, AAV 11, AAV 12, Rh 10, or a rational haploid thereof. In one embodiment of any aspect herein, the rAAV is AAV2. And in one embodiment of any aspect herein, the rAAV exhibits brain-specific tropism. (para. 0046-0047).
The claims are broad for reasonably encompassing a multitude of rAAV capsid serotypes, including AAV9, AAV8, AV7, AAV7m8, AAV6, AAV5, AAV4, AAV3, AAV2, or AAV1, or variants thereof.
Moreover, the claims are broad for reasonably encompassing any route of administration including ones which do not include imaging. Specifically, the invention is local administration utilizing non-invasive imaging.
In one embodiment of any aspect herein, the local introduction is performed simultaneously with non-invasive imaging. Exemplary the non-invasive imaging techniques include intraoperative magnetic resonance image (iMRI)-guided convection enhanced delivery (CED), ultrasound, computed tomography (CT); functional magnetic resonance imaging (fMRI); positron emission tomography (PET); electroencephalography (EEG); magnetoencephalography (MEG); functional near-infrared spectroscopy (fNIRS); and combinations thereof. More specifically, the local introduction comprises introducing about half of the total delivered dose of rAAV vector to each putamen via intraoperative magnetic resonance image (iMRI)-guided convection enhanced delivery (CED). [00013-0014]
The State of the Prior Art, The Level of One of Ordinary Skill and The Level of Predictability in the Art
Considering the mode of administration, the specification simply requires administration of the AAV to the subject by systemic or local means. The art has demonstrated through numerous publications, delivery of nucleic acid vectors in vivo is highly unpredictable for successful human therapy.
At issue in general are organ barriers, failure to persist, side-effects in other organs, T-cell responses, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered. The physiological art is recognized as unpredictable. (MPEP 2164.03.)
Heiss (Movement Disorders, Vol. 34, No. 7, 2019: 2073-2078 + Supplementary Material) demonstrates that dosage/concentration and vector when introducing AAV2-GDNF to a PD brain’s putamen is correlated to the coverage of the putamen. They utilize a dosage less than what is shown in the Working examples and thus obtain in some cases less than the 30% coverage claimed in the present invention. Heiss additionally provides teachings that the route of administration, even the local administration when varied in the putamen, influences the coverage as well (See page 1077, 1st column; p. 1076, Discussion).
Richardson (J Neurol Neurosurg Psychiatry, 2020; 91:1210–1218) describes iMRI monitoring as allowing for safe administration of infusates comprising AAV2 vectors (p. 1216).
Therefore, the scope of enablement is limited to what is described in the Examples of the present invention at the specific dosage and the specific administration route.
The Existence of Working Examples and The Amount of Direction Provided by the Inventor
The independent claims fail to recite the minimal rAAV dosage required to achieve the therapeutic result of at least 30% coverage in the subject’s putamen and stabilization or reduction of PD associated symptoms.
The independent claims fail to recite the administration route as well as the promoter and AAV capsid to achieve the same therapeutic results.
The working examples only provide for an AAV2-GDNF vector with GDNF operably linked to a CMV promoter (Example 1). The AAV2-GDNF is administered at a concentration of 3.3 x 1012 vg/mL with a total dose of 1.2 x 1013 vg across all patients (para. 0539). This was done with iMRI monitoring and CED (para. 00549). The method resulted in 62.5% coverage and reduction in PD related symptoms (para. 00545, 00552).
The Quantity of Any Necessary Experimentation to Make or Use the Invention
The gene therapy art is extremely unpredictable. The unpredictability is manifested in the poor and unpredictable targeting of the gene therapy vectors to target cells (the enormous genus of possible AAV serotypes disclosed ), routes of administration, the transient and unpredictable expression of the transgenes in target cells (the genus of disclosed possible promoters and/or regulatory sequences), and the specific genes to be used for a treatment all factor into placing undue burden for experimentation on one of skill in the art.
As the prior art above discloses, previous AAV2-GDNF vectors have not achieved the same result at their claimed concentrations and total dosages and administration routes, therefore the enablement is limited to what is in the working examples and the results found therein.
In conclusion, the specification fails to provide any guidance as to how an artisan would have dealt with the art-recognized limitations of the claimed method and therefore, limiting the claimed invention to: a method of inhibiting or slowing the progression of Parkinson’s disease in a subject in need thereof comprising administering via infusion with MRI enhanced CED into the putamen an rAAV composition comprising an AAV2 capsid, GDNF transgene operably linked to a CMV, nervous system, or central nervous system promoter, at a concentration of 3.3 x 1012 vg/mL, which achieves up to about 60% coverage of the putamen is proper.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 6, 8, 35, 36, 44, 69 and 72 are rejected 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.
The term “substantially” in claim 6 and 8 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. “Substantially at the same time” could mean at the same time in the same composition, or before or after the composition for an undefined amount of time and “substantially” parallel does not provide a degree to which the cannula cannot be parallel.
Claim 8 recites “the local introduction” however, this term lacks antecedent basis. Claim 8 depends on claim 1 which does not recite “local introduction.” Based on the amendments made, it is interpreted that claim 8 should be dependent on claim 3 or 6 which recites “local introduction.”
Claims 35-36, 69 and 72 recite the terms “mildly” and “moderately.” These are relative terms. The metes and bounds of “mild” and “moderate” are not definite as it could be any number of symptoms or scoring ranges for PD associated symptoms. and the instant specification only describes mildly as an MDS-UPDRS score less than 32. Moreover, the specification only describes moderate as an MDS-UPDRS score equal or greater than 32 (para. 0040).
Claim 44 references the sequences found in Table 1 and 2 in the specification as promoters for the rAAV. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parteFressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). A claim may incorporate by reference to a specific figure or table where there is no practical way to define the invention in words. See MPEP § 2173.05(s).
Therefore, the invention is rejected as being indefinite.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 6, 7, 8, 11, 15, 16, 20, 26, 29, 35, 36, 42, 47-48, 57, 69, 72, and 76 are rejected under 35 U.S.C. 103 as being unpatentable over Heiss (Movement Disorders, Vol. 34, No. 7, 2019: 2073-2078 + Supplementary Material) in view of Martínez-Martín (Parkinsonism and Related Disorders 21 (2015) 50-54) and Goetz (Movement Disorders Vol. 23, No. 15, 2008, pp. 2129–2170).
Regarding claim 1, 42, 47 and 48, Heiss teaches a method of treating individuals with Parkinson’s Disease (PD) (i.e. slowing or inhibiting progression) by administering AAV2-GDNF (i.e. rAAV). As evidenced by the Supplementary materials, GDNF is operably linked to a CMV promoter (See AAV2-GDNF Vector).
Regarding the limitation of putaminal coverage, Heiss teaches that their putaminal coverage was 995 ± 376 mm3 (mean ± SD; range, 315–1,881) which was an average of 26% of the volume (p. 1076, 1st paragraph). If taking the range into account and calculating from 995 as 26% coverage on average with a calculated total volume of putamen is about 3826 mm3, Heiss would demonstrate their infusion of vector covers anywhere between 8% to 49% based on the 315–1,881 mm3 measured range disclosed despite the average being 26%. This range includes the “at least 30%” range of coverage recited in claim 1. Moreover, Heiss states that over 50% can potentially be achieved with higher doses of AAV2-GDNF (p. 1077, 4th paragraph). “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” See MPEP 2144.05. Therefore, it would be prima facie obvious that the method of Heiss would result in the claimed putaminal coverage based on the dosage administered.
Regarding the limitation of the subject not exhibiting an increase in PD-associated symptoms for a least 6 months following the introducing, Heiss teaches UPDRS scores remained stable over the study which lasted at least 6-18 months (Abstract).
Regarding claim 3, Heiss teaches that the AAV2-GDNF is administered via infusion into the putamen (p. 1076, 1st column, p. 1077, 1st column; Figure 1).
Regarding claims 6-7, Heiss teaches gadoteridol (i.e. a contrast agent) is coinfused with the rAAV composition (Abstract). Heiss utilizes intraoperative MRI (iMRI) guided convection-enhanced delivery (CED) (p. 1074, 2nd column).
Regarding claim 8, Heiss teaches the composition is administered bilaterally in the putamen with the cannula trajectories being perpendicular to the long axis of each putamen (i.e. parallel to the A-P axis) (Fig. 1, p. 1077, 1st column). Heiss further aims to produce a follow up clinical trial using larger infusion volumes and a posterior surgical approach along the putamen’s long axis to increase coverage sufficiently to affect the relevant motor circuitry of the postcommissural putamen (p. 1077, 1st column).
Therefore, it would have been obvious to one of ordinary skill in the art to try posterior parallel surgical approaches near the occipital bone as claimed in claim 8.
Regarding claim 11, Heiss teaches gadoteridol (i.e. a contrast agent) is coinfused with the rAAV composition (Abstract). Therefore, the agent is in the same composition as the rAAV.
Regarding claim 15, as discussed above, Heiss provides teachings which indicate that the amount of at least 50% is achievable through a higher dosage of the present invention (p. 1077, 4th paragraph), therefore reading on coverage such as 60%.
Regarding claim 16, Heiss does not utilize the MDS-UPDRS score, but rather a UPDRS score. As evidenced in the Supplementary Information, UPDRS scores of greater than or equal to 30 were required for participation and were stable over the 6-18 month period. As disclosed by the instant specification, “Historically, researchers use the UPDRS to measure therapeutic benefits from a given therapy in a unified and accepted rating system. The MDS-UPDRS is an updated version of the UPDRS took aspects of nonmotor functioning out of each subcategory” (p. 24).
Martínez-Martín teaches that the MDS-UPDRS revision to UPDRS retains the strength of UPDRS and adds some elements not covered by this scale, resolves ambiguities and provides detailed instructions (p. 52-53, bridging paragraph). For trained clinicians it is not difficult to link UPDRS motor scores with a severity stage however, such precision cannot be achieved by other than experts in movement disorders. Martínez-Martín teaches cut-off points for MDS-UPDRS in Table 4.
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It would have been obvious to one of ordinary skill in the art to observe and record initial and final scores for PD patients with an updated MDS-UPDRS rather than UPDRS. An artisan would be motivated to do so as Martínez-Martín details many advantages to the revised MDS-UPDRS such as it resolves ambiguities and provides detailed instructions (p. 52-53, bridging paragraph). Regarding the limitation of less than 32 on the MDS-UPDRS scale, as this correlates to less than moderate/severe in Part III as described in the above table and in the instant specification (para. 00549), Heiss teaches on this limitation as an artisan would reasonably expect the patients of Heiss which have scores 30 or greater, which as evidenced by Goetz, MDS-UPDRS rates 65 items in comparison to the 55 original (p. 2130, last paragraph; p. 2132, 1st paragraph) which would result in a possible increase in score from the original UPDRS (p. 2135, 2nd column), and also the findings that there is a “high correlation between the total scores on the original UPDRS and MDS-UPDRS” which “demonstrates that the two scales are measuring the same overall entity of PD,” (p. 2137, 1st paragraph). Therefore, Heiss’ criteria would overlap in score. Heiss additionally demonstrates that their UPDRS score remained stable over the 18 month period (i.e. not exhibit a substantial increase in PD-associated symptoms).
Regarding claims 20 and 26, as discussed above in the combination of Heiss, Martínez-Martín and Goetz, it would be obvious to give an initial score on the MDS-UPDRS scale prior to administration and then a second MDS-UPDRS score which is not substantially higher than the initial score or stabilized.
Regarding claim 29, as discussed above, Heiss, Martínez-Martín and Goetz make obvious the active steps of the method of claim 1 and the utilization of MDS-UPDRS scores. It would be obvious to one of ordinary skill in the art to reasonably expect a reduction of the initial MDS-UPDRS when each and every limitation is made obvious by the prior art cited. The same method steps would yield the same predictable results.
Regarding claim 35, as discussed above, Heiss, Martínez-Martín and Goetz make obvious the active steps of the method of claim 1 and the utilization of MDS-UPDRS scores. Moreover, Heiss teaches that the patients utilized were diagnosed at least 5 years with PD (Supplementary Material, p. 1). Therefore, the ranges overlap at 5 years and Heiss reads on the claimed limitation.
Regarding claim 36, Heiss teaches that UPDRS scores are determined prior to introduction, therefore determining severity as mild or moderate prior to the rAAV administration (Supplementary information, p. 1).
Regarding claim 57, Heiss teaches that the PD patients were treated with levodopa prior to the administration (Supplementary, p. 1).
Regarding claim 69, as discussed above Heiss, Martínez-Martín and Goetz make obvious the active steps of the method of claim 1 and the utilization of MDS-UPDRS scores. Moreover, Heiss teaches that the score of the UPDRS scale is stabilized at least 6 months (Abstract). As for the “mildly” limitation in the preamble, the metes and bounds of “mildly” are not definite as discussed in the above 112b rejection and the instant specification only describes mildly as an MDS-UPDRS score less than 32. Based on this interpretation, as discussed above, Heiss reads on patents both mildly and moderately effected with patients having at least scores of 30 and Martínez-Martín stating that UPDRS and MDS-UPDRS have correlation in overall total score.
Regarding claim 72, as discussed above Heiss, Martínez-Martín and Goetz make obvious the active steps of the method of claim 1 and the utilization of MDS-UPDRS scores. Regarding the “moderately affected” limitation in the preamble, the metes and bounds of “moderate” are not definite as discussed in the above 112b rejection and the instant specification only describes moderate as an MDS-UPDRS score equal or greater than 32 (para. 0040). Based on this interpretation, as discussed above, Heiss reads on patents both mildly and moderately effected with patients having at least scores of 30 and Martínez-Martín stating that UPDRS and MDS-UPDRS have correlation in overall total score. Moreover, as the above references read on each and every active method step in claim 72, the same method steps would yield the same predictable results with a reasonable expectation of success.
Regarding claim 76, Heiss teaches a method of treating individuals with Parkinson’s Disease (PD) (i.e. slowing or inhibiting progression) by administering AAV2-GDNF (i.e. rAAV). As evidenced by the Supplementary materials, GDNF is operably linked to a CMV promoter (See AAV2-GDNF Vector). As the rAAV is administered in a solution, it is interpreted that it is in a pharmaceutically acceptable carrier. Therefore, Heiss teaches the composition of claim 76.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 44 are rejected under 35 U.S.C. 103 as being unpatentable over Heiss (Movement Disorders, Vol. 34, No. 7, 2019: 2073-2078 + Supplementary Material) as applied to claim 1 and 42 above, and in further view of Braee (WO2022049385; Priority Date of 04-09-2020)
As discussed in the above 103 rejection and incorporated herein in its entirety, Heiss makes a method of treating a patient with PD with a AAV2-GDNF wherein the promoter that GDNF is operably linked to is CMV.
However, Heiss does not teach that the promoter is a CNS or NS specific promoter from Table 1 or Table 2 of the specification.
Braae teaches a NS specific promoter sequence, SEQ ID NO: 1, which has a 100% identity to SEQ ID NO: 3 in Table 1 of the present application as shown below.
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Braae teaches that this and other NS specific promoters on p. 110 of their disclosure in Table 1. The promoters are utilized in gene therapy vectors for treatment of neurological disorders such as Parkinson’s Disease (p. 57, 87, 91)
It would have been obvious to utilize the promoter of Braae which has a 100% sequence identity to SEQ ID NO: 3 in the construct described by Heiss for the purpose of treating PD with a reasonable expectation of success. An artisan would be motivated to substitute the Braae promoter for the CMV promoter as it is a known promoter to target the NS for gene therapy regarding Parkinson’s Disease.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 46 are rejected under 35 U.S.C. 103 as being unpatentable over Heiss (Movement Disorders, Vol. 34, No. 7, 2019: 2073-2078 + Supplementary Material) as applied to claim 1 above, and in further view of Pukhrambam (US2017252376)
As discussed in the above 103 rejection and incorporated herein in its entirety, Heiss makes a method of treating a patient with PD with a AAV2-GDNF wherein the promoter that GDNF is operably linked to is CMV.
However, Heiss does not teach the sequence of the GDNF transgene nor its percent identity to SEQ ID NO: 1 of the present application.
As shown below, Pukhrambam (which corresponds to ID No. BEH42869) teaches SEQ ID NO: 47 as a cDNA for GDNF which has a 100% identity to SEQ ID NO: 1 of the present invention.
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It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize the cDNA for GDNF of Pukhrambam in place of the GDNF sequence in Heiss with a reasonable expectation of success. An artisan would be motivated to do so as both are known alternative sequences which encode for the same protein, GDNF.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 52 and 77 are rejected under 35 U.S.C. 103 as being unpatentable over Heiss (Movement Disorders, Vol. 34, No. 7, 2019: 2073-2078 + Supplementary Material) in view of Martínez-Martín (Parkinsonism and Related Disorders 21 (2015) 50-54) and Goetz (Movement Disorders Vol. 23, No. 15, 2008, pp. 2129–2170) as applied to claims 1 and 76 above, and in further view of Richardson (J Neurol Neurosurg Psychiatry, 2020; 91:1210–1218.)
As discussed in the above 103 rejection and incorporated herein in its entirety, Heiss makes a method of treating a patient with mild or moderate PD as detailed by MDS-UPDRS with a AAV2-GDNF wherein the promoter that GDNF is operably linked to is CMV. Moreover, Heiss teaches that 9x1010 vg, 3x1011 vg and 9x1011 vg were administered to subjects wherein the infusion rate reached a maximum of 5 µL/min (Supplemental Information, p. 1, 4). Moreover, Heiss states that over 50% coverage of the putamen can potentially be achieved with higher doses of AAV2-GDNF (p. 1077, 4th paragraph).
However, regarding claims 52 and 77, Heiss does not teach 3x10¹² vg/mL to about 4x 10¹² vg/mL in the composition.
Richardson teaches various gene therapy trials involving vectors encoding GDNF, hAADC, and others for the treatment of PD (Abstract, p. 1211). Richardson teaches different known trials which have vector concentrations of 8.3 x 1011 vg/mL, 8.3 x 1011 vg/mL, 2.6 x 1012 vg/mL, and Up to 2.6 x 1012 vg/mL (Figure 3). Cohort 1 of PD1101 in Figure 3 which has vector concentrations of 8.3 x 1011 vg/mL is known to be similar to that of the fusion parameters of Heiss (p. 1216, 3rd paragraph).
It would have been obvious to one of ordinary skill in the art to provide 3x10¹² vg/mL to about 4x 10¹² vg/mL in a composition of AAV2-GDNF as taught by Heiss in order to treat PD with a reasonable expectation of success. An artisan would be motivated to optimize the concentrations by increasing the concentrations beyond what is taught by Richardson, as Heiss teaches higher percentages of putamen coverage can potentially be achieved with higher doses of AAV2-GDNF (p. 1077, 4th paragraph).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Conclusion
No claims are allowed.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634
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