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 (1-13, 19 and 20) in the reply filed on Feb. 19, 2026 is acknowledged.
Claims 1-13, 19 and 20 are examined below.
Priority
The application claims priority to provisional applications 63/419,243 filed Oct. 25, 2022 and 63/173876, filed April 12, 2021; as such the earliest possible priority date is Oct. 25, 2022.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. It is noted that the required language is already present in the specification.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
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
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.
Claims 1-13, 19 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for increasing outflow of cerebral spinal fluid (CSF) from CNS through enlargement/repair of nasopharymgeal lymphatic plexus (NPLP) through administration of AAV-VEGF-C to the intracranial cavity, does not reasonably provide enablement for methods of increasing outflow of CSF through administration of any “NPLP flow agent” (see 112/2nd rejection below with respect to NPLP flow agent) in an undisclosed location and using anything other than an AAV vector encoding a VEGFR3 agonist, such as VEGF-C. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention.
PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is “undue”, not “experimentation”. The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apis. 1986) at 547 the court recited eight factors:
1) the nature of the invention, 2) the breadth of the claims, 3) the state of the prior art, 4) the predictability or unpredictability of the art, 5) the relative skill of those in the art, 6) the amount of direction or guidance provided, 7) the presence or absence of working examples, 8) the quantity of experimentation necessary.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108,427 F.2d 833,839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1) The nature of the invention and 2) the breadth of the claims
The claims are drawn to methods of increasing outflow of CSF through administration of a NPLP flow agent in an effective amount to repair or enlarge the NPLP of the subject, thereby increasing CSF outflow from the CNS to systemic circulation in the subject.
Thus, the claims taken together with the specification assert that Applicant is claiming that any NPLP flow agent, in any form (protein or genetic vector encoding the flow agent polypeptide, analog, variant or fragment thereof), administered through any route, will repair/enlarge the NPLP and thereby increase outflow of CSF from the CNS.
3) the state of the art, 4) unpredictability of the art and 5) the relative skill of those in the art
The relative skill of those in the art is high, generally an advanced degree with knowledge in neuroanatomy and physiology.
That factor is outweighed, however, by the unpredictable nature of the art and the current state of the art.
As taught by Pollay in 2010, “the structures responsible for the return of CSF to general circulation is based on somewhat conflicting evidence as to their location, anatomical features, and functional capabilities.” (pg. 1, Introduction). Pollay concludes that the evidence as of 2010 supported the important of the cranial arachnoid villi and lymphatic drainage system in draining CSF from the subarachnoid space. (pg. 18, Conclusion). By 2021, the understanding of where and how CSF drains from the subarachnoid space had been altered, now including support for drainage across the cribiform plate to nasal lymphatics, along the optic nerve to oribital lymphatics, through basal foramina, along lumbar and sacral nerves to lymphatics (Proulx, Cell Molecular Life Sci, 2021, pg. 2449, Fig. 5, Abstract). Proulx continues, “as is clear from this review, there is overwhelming historical evidence for perineural outflow pathways for CSF that have barely been acknowledged in several recent publications. Of the three major proposed mechanism for CSF outflow, the extracranial portion of cranial nerves and the region of the spinal near the dorsal root ganglions are the only routes where barriers at either the arachnoid or endothelial cell layers have consistently been found to be lacking, allowing for bulk outflow as shown in physiological studies….Ultimately, the question in humans will not be definitely answered until a method of sensitively and specifically imaging the egress of CSF can be established in the clinic. (para. bridging 2449-2450). Proulx concludes “The alignment of evidence across mammalian species should, however, be sufficient to make clinicians and researchers critically question the textbook view of CSF outflow and to seek an improved understanding of the clearance pathways to the lymphatic system and the potential implications of these connections to the periphery for multiple neurological disorders.” (pg. 2450.
As applicants further explain in their background section, Ma found meningeal lymphatic vessels (mLVs) in mice, postulating them as an additional drainage route; however, they were unable to follow CSF reuptake and drainage through this route. Ma postulated that the mLVs would drain along the cranial nerves. Applicants discovered that basolateral mLVs are the main route of CSF drainage; that the NPLP is a hub for CSF drainage through the skull base, including the cribiform plate; and that CSF drainage through the NPLP/medial side deep cervical lymphatic vessel (M-dcLV) route is greater and faster than through the basolateral mLV/lateral side (L)-dcLV route. (specification, pg. 1-4) These findings, support the conclusion that the NPLP is of paramount importance to CSF drainage and that this drainage system becomes impaired with age. It earned the inventors a Nature publication in 2025. (Hokyung Jin et al.)
6) the amount of direction and guidance provided and 7) the presence and absence of working examples
Applicant disclosure recites that any NPLP flow agent can be administered in any way and that this administration will result in the increased outflow of CSF. Applicants indicate that VEGFR3 agonists, such as VEGF-C, VEGF-D; and FGF-2, IGF-1; HGF; ET-1; angiopoietin-1, Tie2 agonist, neurophilins, prostaglandin E2 and analogues, variants or fragments of these function as NPLP flow agents.
Applicants’ examples demonstrate that intracranial cavity administration of AAV-VEGF-C in young and old mice effectively increases the outflow of CSF. (p. 42-45, Ex. 13 and 15). Applicants’ other examples are devoted to elucidation of the flow of CSF in that basolateral mLVs are the main route of CSF drainage; that the NPLP is a hub for CSF drainage through the skull base, including the cribiform plate; and that CSF drainage through the NPLP/medial side deep cervical lymphatic vessel (M-dcLV) route is greater and faster than through the basolateral mLV/lateral side (L)-dcLV route.
There are no examples using any NPLP flow agent other than AAV-mVEGF-C administered to the intracranial cavity, only assertions that any NPLP flow agent, protein or viral vector encoding the protein, analogues, variants or fragments can be used with many routes of administration (see claims 9, 11, 13, noting that claim 1 is not limited in any way to a specific administration route).
Thus, the person of ordinary skill in this art has an understanding that CSF egress is a complicated subject and our understanding of it is incomplete; that inventors have discovered that basolateral mLVs are the main route of CSF drainage; that the NPLP is a hub for CSF drainage through the skull base, including the cribiform plate; and that CSF drainage through the NPLP/medial side deep cervical lymphatic vessel (M-dcLV) route is greater and faster than through the basolateral mLV/lateral side (L)-dcLV route.
That person does not have an understanding that any NPLP flow agent with any type of administration will work to increase CSF outflow. That person does not have an understanding of what constitutes a NPLP flow agent.
There is no way for one skill in the art to know, a priori, that even the NPLP flow agent enumerated by applicants will work, that administration other than to the intracranial cavity will work or even that administration of the protein, rather than the AAV encoding the protein will work. Thus, the state of the prior art does not support the broad scope of the rejected claims.
8) The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept the assertion that any NPLP flow agent with any type of administration will work to increase CSF outflow as inferred in the claims and contemplated by the specification.
Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable." (42 USPQ 2d 1001, Fed. Circuit 1997).
To practice the invention of the instant claims required undue experimentation due to unpredictability in the understanding of the complex nature of increasing outflow of CSF through administration of a NPLP flow agent in an effective amount to repair or enlarge the NPLP of the subject, thereby increasing CSF outflow from the CNS to systemic circulation. While applicants have made a valuable discovery in this area, there is still work to be done to determine what agent will function as NPLP flow agents, where and how they can be administered and whether administration of protein will be effective or if administration of an AVV encoding that protein is required.
In light of the above discussion, the instant claims do not comply with the enablement requirement of 35 U.S.C. § 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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.
Claims 1-3, 7, 9-13, 19 and 20 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 independent claim recites administration of a “NPLP flow agent”. This term is not definite, as it is defined by its function and what will function in that way is not well-understood in the art. (as explained above). The specification does not provide a definition of this term. Paras. [0096]-[0105] discuss NPLP Flow Agents, indicating that VEGFR3 agonists, such as VEGF-C and VEGF-D, are NPLP flow agents. The specification provides exemplary, non-limiting NPLP Agents that include (but are not limited to) FGF-2, IGF-1; HGF; ET-1; angiopoietin-1, Tie2 agonist, neurophilins, prostaglandin E2 and analogues, variants or fragments of these function as NPLP flow agents. As such, one of ordinary skill in the art would not know what, in addition to these recited NPLP flow agents, might be encompassed by the term “NPLP flow agent”.
Dependent claims 2, 3, 7, 9-13, 19 and 20 do not resolve this indefiniteness and are rejected on the same basis.
The term “near NPLP-dCLV space” in claim 9 is a relative term which renders the claim indefinite. The term “near” 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.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TERESA E KNIGHT whose telephone number is (571)272-2840. The examiner can normally be reached Monday-Friday 9-4.
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/TERESA E KNIGHT/ Primary Examiner, Art Unit 1634
/CHRISTOPHER M BABIC/ Supervisory Patent Examiner, Art Unit 1633