DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I, claimed in claims 1, 6-8, 10, 12, 14, 17-19, 23, 25-26, 28 and 30-31 was previously acknowledged. Election was made without traverse of VEGF-c (lymphangiogenic growth factor), amyloid beta antibody (neurological therapeutic agent) and AD (neurological disease).
In the reply filed 10/22/25, Applicants amended claims 119, 23, 25 and added new claim 65. Claims 6-8, 10, 12, 14, 17-18 and 33-34 were canceled.
Claims 1, 19, 23, 25-26, 28, 30-31 and 65 are pending and under consideration.
This Office Action is made non-final due to the Office’s prior omission of a double patenting rejection.
Claim Rejections-Withdrawn
The rejection of claims 1, 6-8, 10, 12, 23, 25-26, 28 and 30-31 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,944,665 in view of Healthline (https://www.healthline.com/health/pandas-syndrome 3/30/19) is withdrawn due to amendment of the claims.
Claim Rejections - 35 USC § 112-NEW
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
NEW Claim 65 is rejected 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. Claim 65 fails to further limit and fails to include all the limitations of claim 1 because claim 1 is drawn to VEGF-c. Claim 1 does not recite VEGF-c variants and the instant specification does not define VEGF-c to include variants.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112-Maintained
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.
The rejection of claims 1, 23, 25-26, 28 and 30-31 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 maintained and extended to NEW claim 65. 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. 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.
Scope of the claimed genus
Claim 1 is drawn to increasing clearance of amyloid beta or amyloid precursor protein from the CNS, reducing an aggregate of amyloid beta in the CNS, reducing neurite dystrophy in the subject, reducing microglial inflammatory response in the CNS or treating all neurological diseases with a flow modulator and neurological therapeutic, wherein the subject has a neurological disease, wherein the subject has a neurological disease or disorder associated with accumulation of amyloid beta plaques, the method comprising administering an effective amount of a flow modulator comprising VEGF-c or a polynucleotide encoding VEGF-c and administering an effective amount of a neurological therapeutic agent to the central nervous system of the subject, wherein the neurological therapeutic agent comprises an antibody that binds to amyloid beta or an antigen binding fragment thereof.
The USPTO provides claim terms with broadest reasonable interpretation in light of the specification.
Assessment of whether species are support in the original specification
The instant specification discloses the flow modulator of VEGF-c and neurological therapeutic agent, aducanumab had the claimed function of treating AD and reducing aggregation of amyloid beta.
There was no disclosure of other antibodies or antigen binding fragments thereof.
In summary, for these reasons, the skilled artisan would reasonably conclude that the inventor(s), at the time the application was filed, had possession of VEGF-c and aducanumab at the time the invention was filed.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that 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.
In the instant case, the disclosure of VEGF-c and the amyloid beta antibody aducanumab is not representative of the genus of antibodies that bind to amyloid beta or antigen binding fragments thereof because the genus is large.
Identifying characteristics and structure/function correlation
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe the structural, physical and/or chemical properties of the neurological therapeutic thereof that has the claimed functions.
In conclusion, for the reasons presented above, the skilled artisan would reasonably conclude that the inventors, at the time the application was filed had full possession of the flow modulator VEGF-c and the neurological therapeutic agent aducanumab.
Response to Arguments
Applicant's arguments filed 10/22/25 have been fully considered but they are not persuasive. Applicants argue that disclosure of VEGF-c and aducanumab sufficiently represents the genus o VEGF-c and an antibody that binds to amyloid beta or an antigen binding fragment thereof. The skilled artisan would reasonably conclude the inventors had full possession of the flow modulator and neurological therapeutic agent as defined in the present claims.
These arguments were considered but are not persuasive because the genus of neurological therapeutic agents is quite large including any antibody that binds to amyloid beta or antigen binding fragments thereof. A person of ordinary skill in the art would not reasonably conclude that the inventors had full possession of the therapeutic agent.
Claim Rejections - 35 USC § 103-Maintained
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
The rejection of claims 1, 19, 23, 25-26, 28, 30-31 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Kipnis et al. (WO2017210343) in view of Sevigny et al. (Nature 537, 50-56 (2016) is maintained.
With respect to claims 1 and 25, Kipnis et al. teach a method for increasing flow of fluid in the central nervous system of a subject comprising VEGFR3 agonist (claim 1 and Abstract).Kipnis et al. also teach and claim reducing amyloid beta plaques in a subject comprising administering a VEGFR3 agonist to the meningeal space (claim 20). Kipnis et al. claim a method of increasing clearance of a molecule from the CNS comprising administering VEGFR3 agonist to the meningeal space of the subject (claim 33). Kipnis et al. teach 34A-C that discloses VEGF-c expression in the CNS or a mouse model of AD ameliorated dementia symptoms ([0046, 0179, 0189-0190. Kipnis et al. teach a method reducing the number and/or volume of amyloid plaques [0140]. Kipnis et al. teach and claim administering the VEGFR3 agonist to the meningeal space of a subject ([0010]).
Kipnis et al. does not teach administering an effective amount of a neurological agent comprising an antibody that binds to amyloid beta to the CNS of the subject. However, the teachings of Sevigny et al. cures this deficiency.
Sevigny et al. teach aducanumab human monoclonal antibody that selectively targets aggregated amyloid beta (Abstract). Sevigny et al. teach monthy IV infusions of aducanumab reduced amyloid beta in a time and dose dependent manner accompanied by a slowing of clinical decline (Abstract,Table 1, Figure 1-4). Sevigny et al. teach aducanumab was shown to enter the brain (Abstract).
It would have been obvious to one or ordinary skill in the art at the time of the invention to combine VEGF-c from Kipnis et al. and aducanumab from Sevigny et al. for treatment of AD and clearance of aggregated amyloid plaques. MPEP 2144.06 states: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, Ki[nis et al. teach VEGF-c for treatment of AD and clearance of amyloid beta plaques and Sevigny et al. teach aducanumab for treatment of AD and clearance of amyloid beta plaques, therefore the prior art teaches the compositions useful for the same purpose. A reasonable expectation of success is expected given that each component (VEGF-c ad aducanumab are treatments for AD and aggregated plaque clearance in AD).
With respect to claim 19, aducanumab is an antibody that binds amyloid beta.
With respect to the limitations of claim 23 “flow modulator increases the diameter….or wherein the method reduces the aggregate of amyloid beta by at least 5%”, the combination of Kipnis et al. and Sevigny et al. would necessarily have all of the activities and properties of the composition of claim 1. The MPEP § 2112 states: “Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evidence or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference ‘[t]he PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on inherency’ under 35 U.S.C. 102, on prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same…[footnote omitted].” The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzqerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430,433- 34 (CCPA 1977)).” In other words, Kipnis et al. and Sevigny et al. make obvious administering a flow modulator (VEGF-c) and Sevigny et al. teach administering a neurotherapeutic agent (aducanumab) to a subject with AD. Therefore the administering the same composition to the same patient population would necessarily result in increased diameter of meningeal lymphatic vessels or reduction in amyloid beta aggregates. Moreover, MPEP 2112.01 states: “Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Importantly, Kipnis et al. teach in some embodiments, the diameter of the meningeal lymphatic vessel is increased by at least 5%, 10%, 15%, 20%, 30%, 50% or more (e.g., when post-administration is compared to pre-administration) [0008].
With respect to claim 26, Sevigny et al. teach intravenous infusion of aducanumab (neurological therapeutic agent). Sevigny et al. teach aducanumab was shown to enter the brain (Abstract), meeting the limitation of “contact with CSF”. Kipnis et al. claim a method of increasing clearance of a molecule from the CNS comprising administering VEGFR3 agonist to the meningeal space of the subject (claim 33,[0008]).
With respect to claims 28 and 30-31, it would have been obvious to a person of ordinary skill in the art to optimize the route of delivery and when the compositions are delivered. A person of ordinary skill in the art would have a motivation to administer in the same pharmaceutical composition for ease of administration resulting in concurrent administration. If the agents are administered in the same pharmaceutical composition, the route would necessarily be the same. There is a reasonable expectation of success given that the agents are known in the art and are administered for the same purpose as instantly claimed. Furthermore, there are only three ways to administer the flow modulator, prior, concurrently or subsequent to the aducanumab.
With respect to new claim 65, Kipnis et al. teach staining in meningeal lymphatic vessels from old mice revealed that treatment with VEGF-C156S had a significant effect on vessel diameter (FIG. 26).
Response to Arguments
Applicant's arguments filed 10/22/25 have been fully considered but they are not persuasive. Applicants argue that the instant application shows that administration of an amyloid beta antibody surprisingly increased lymphatic vessel branching while administration of VEGF-c did not result in such effect (see Example 1, [0364] and Fig. 1E. Applicants argue this technical effect was not suggested by any of the cited references. Applicants argue that mice that received both amyloid beta antibody and VEGF-c had increased meningeal lymphatic coverage compared to control mice and had higher meningeal lymphatic coverage that mice receiving VEGF-c alone (Fig. 1G). Applicants argue that the effects of an anti-amyloid beta antibody on the lymphatic vessels when co-administered with bona fide lymphangiogenic growth factor is clearly unexpected.
These arguments were considered but are not persuasive because the results are not commensurate in scope with the claims. In particular, the claims are drawn to VEGF-c and an antibody that binds amyloid beta or an antigen binding fragment thereof. However, Example 1 is drawn to VEGF-c and aducanumab. Therefore, the specification demonstrates the effect only for a single specific antibody. The showing of a single species does not support a conclusion that all of the genus of antibodies and antigen binding fragments that bind amyloid beta would have exhibit the same results. Importantly, Fig. 1G does not show that there is a significant difference with a P-value of 0.0870. As indicated above, MPEP 2144.06 states: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, Ki[nis et al. teach VEGF-c for treatment of AD and clearance of amyloid beta plaques and Sevigny et al. teach aducanumab for treatment of AD and clearance of amyloid beta plaques, therefore the prior art teaches the compositions useful for the same purpose. A reasonable expectation of success is expected given that each component (VEGF-c ad aducanumab are treatments for AD and aggregated plaque clearance in AD).
For the reasons presented above, the rejection is maintained.
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.
Claims 1, 19, 23, 25-26, 28, 30-31 and 65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-7, 12-14, 16, 18-19, 21-24, 30-31, 58, 60 and 63 of copending Application No. 17794,338 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. The copending Application claims a method of modulating an activity of lymphatic endothelial cells, a brain myeloid cell (microglia)…comprising administering an effective amount of a flow modulator that increases the fluid flow in the CNS and an effective amount of a neurological therapeutic agent, (claim 1), wherein the neurological disease is AD (claim 16), wherein the therapeutic agent comprises an antibody or antigen binding fragment thereof that binds to a protein or a peptide that forms pathological aggregate (claim 22), wherein the peptide or protein is amyloid beta precursor protein or amyloid beta (claims 22-23), wherein the flow modulator is VEGF-c administered by administered by ICM injection (claim 30). Claim 63 of the copending application claim increasing clearance of a molecule from the CNS, reducing a microglial inflammatory response, treating a neurological disease…comprising administering a flow modulator and neurological therapeutic. Therefore, the copending application anticipates the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/TARA L MARTINEZ/Examiner, Art Unit 1654