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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/US2020/056285 filed October 19, 2020, which claims the benefit of US Provisional Application No. 62/923,015 filed October 18, 2019. All claims have been given an effective filing date of October 18, 2019.
Election/Restriction
Applicant's species election of A) dipyridamole in the reply filed on December 10, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 40 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 10, 2025.
Claim Status
Claim listing filed on March 25, 2024 is pending. Claims 4-6, 10-16, 22-24, 26-27, 30, 34-39, and 43 are canceled. Claims 1, 3, 7-9, 17-18, 21, 25, 28-29, 31-32, and 40-42 are amended. Claim 40 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected species. Claims 1-3, 7-9, 17-21, 25, 28-29, 31-33, and 41-42 are examined upon their merits.
Information Disclosure Statement
The information disclosure statements filed on 01/02/2025, 07/23/2025, 08/08/2025, and 02/04/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: page 2, line 12 recites “the remains a need” and should recite “there remains a need.”
Appropriate correction is required. Applicant is urged to carefully review the specification for additional informalities.
Claim Objections
Claims 8, 25, 33, and 42 are objected to because of the following informalities:
Claim 8 repeats the term “nucleotides.”
Claim 25 depends from Claim 41. MPEP § 608.01(n).IV states that a series of singular dependent claims is permissible in which a dependent claim refers to a preceding claim which, in turn, refers to another preceding claim. Claim 25 does not refer to a preceding claim.
Claim 33 references formula I. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure "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" (see MPEP § 2173.05(s)). Formula I from the specification is not an exceptional circumstance and can be practically written into the claim in order to make the claims complete in themselves.
Claim 42 recites “a composition comprising an effective amount an inhibitor” and should recite “a composition comprising an effective amount of an inhibitor.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-3, 7-9, 17-21, 25, 28-29, 31-33, and 41-42 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.
Claims 1 and 18 are rejected for recitation of intended results/effects that do not confer some structural, material, or manipulative difference on the scope of the claim. Claim 1 recites “to reduce transcellular transport of one or more cell penetrating antibodies into a tissue of the subject” and Claim 18 recites “to reduce transduction of one or more cell penetrating antibodies into cells of the subject.” It is unclear whether or not reducing transcellular transport or transduction of one or more cell penetrating antibodies is required for infringement because this limitation adds no steps over the step of administering an inhibitor of a nucleoside transporter. It is unclear if all inhibitors of a nucleoside transporter inherently reduce transcellular transport or transduction of one or more cell penetrating antibodies or if this limitation narrows the scope to a subset of nucleoside transport inhibitors capable of this function. The claims are directed to an intended result obtained, and the scope of the method step is unclear (MPEP 2173.05(g)). For the purpose of compact prosecution, it is interpreted that all inhibitors of a nucleoside transporter inherently reduce transcellular transport or transduction of one or more cell penetrating antibodies into a tissue of the subject, and the intended result does not confer a structural, material, or manipulative difference on the scope of the method comprising administering an inhibitor of a nucleoside transporter.
Claim 1 recites “reduce transcellular transport”; Claim 3 recites “the inhibitor reduces transport”; Claim 17 recites “reduce one or more symptoms”; Clam 18 recites “reduce transduction”; and Claim 42 recites “reduce one or more symptoms.” These phrases comprise indefinite relative terminology, specifically the term “reduce” (MPEP § 2173.05(b)). How is a reduction in transcellular transport, transduction, and symptoms measured? What is the threshold of reduction (i.e. 10%, 50%, 80%)? What are the reductions relative to (i.e. a healthy subject or an untreated subject)? The specification does not provide a definition of “reduce” in such a way that one of ordinary skill in the art would understand what is claimed. Claims 1-3, 7-9, 17-21, 25, 28-29, 31-33, and 41-42 are rejected for indefinite relative terminology.
Claim 17 is rejected for recitation of intended results/effects that do not confer some structural, material, or manipulative difference on the scope of the claim. Claim 17 recites “administering to the subject an effective amount of an inhibitor of a nucleoside transporter to reduce one or more symptoms of the CNS lupus.” Specifically, “to reduce one or more symptoms of CNS lupus” is an intended result. It is unclear how this intended result changes the scope of the method of Claim 1 comprising administering the inhibitor of a nucleoside transporter to a subject with CNS lupus. For the purpose of compact prosecution, it is interpreted that reducing one or more symptoms of the CNS lupus is an inherent property of the method step recited in Claim 1 comprising administering the inhibitor of a nucleoside transporter.
Claim 1 recites “cell penetrating antibodies”; Claim 7 recites “nuclear penetrating antibodies”; Claim 8 recites “the antibodies bind to nucleic acids, nucleotides, or a combination thereof”; Claim 9 recites “the antibodies are internalized…by the nucleoside transporter”; Claim 18 recites “cell penetrating antibodies.” In all of these instances, the antibodies are defined by what they do (penetrate cells / penetrate nucleus / bind nucleic acids / internalized by the nucleoside transporter) rather than by what they are (MPEP § 2173.05(g)). Claims 2-3, 17, 19-21, 28-29, 31-33, and 41- 42 depend from Claims 1, 7-9, and 18 without further defining the claimed antibodies. The specification defines “cell penetrating antibody” as an immunoglobulin protein, fragment, or variant thereof that is transported across the cell membrane of living mammalian cells (page 7, lines 14-16). Similarly, the specification defines “nuclear penetrating antibody” as an antibody, or antigen binding fragment or molecule thereof that is transported into the nucleus of living mammalian cells and binds to a target therein (page 7, lines 21-24). These definitions recite results obtained without any required structure, and the metes and bounds of these antibodies cannot be readily determined.
Claim 18 recites wherein the inhibitor of the nucleoside transporter is dipyridamole or “pharmaceutically active analogue thereof.” The specification defines non-limiting examples of dipyridamole analogues (page 18, lines 22-26 and Tables 1-5); however, “analogue” is not defined in the specification such that one of ordinary skill would understand the structural metes and bounds required by the claim. Therefore, a “pharmaceutically active analogue thereof” requires the activity of dipyridamole but with no structural limitations. The broadest reasonable interpretation is that the claim encompasses any molecule that has dipyridamole activity which is indefinite functional language (MPEP § 2173.05(g)). Claims 18-21 are rejected for the indefinite term “analogue.”
Claim 29 recites “pyrimidopyrimidine or pteridine derivative” which is interpreted as a pyrimidopyrimidine derivative or a pteridine derivative. However, “derivative” is not defined in the specification such that one of ordinary skill would understand the structural metes and bounds required by the claim. The structural limitations of “derivative” are indefinite. Claim 29 further recites a “pharmaceutically active analogue thereof” which, as explained above in regard to Claim 18, requires the activity of dipyridamole but with no structural limitations. The broadest reasonable interpretation is that the claim encompasses any molecule that has dipyridamole activity which is indefinite functional language (MPEP § 2173.05(g)). Claim 32 also recites the indefinite term “dipyridamole analogue.” Claims 29 and 32 are rejected for the indefinite terms “derivative” and “analogue.”
Claim 33 defines wherein the dipyridamole analogue is a compound of formula I. However, formula I does not define the structure of R4 (pages 19-20, specifically page 19 line 18). Therefore, formula I is non-limiting in structure, and the metes and bounds of Claim 33 are indefinite.
Claim 21 recites the limitation "the tissue" in line 2. There is insufficient antecedent basis for this limitation in the claim, because “tissue” is not defined in the preceding claim (Claim 18).
Claim 28 is indefinite because it recites the abbreviation “ENT” without defining the abbreviation in the claims. For the purpose of compact prosecution, “ENT” is interpreted as “Equilibrative Nucleoside Transporter.” Appropriate correction is required.
Claim 29 recites in the last bullet point “wherein the oligonucleotide inhibitor is an antisense RNA or DNA, siRNA or siDNA, miRNA, miRNA mimic, shRNA or DNA and Chimeric Antisense DNA or RNA.” It is unclear what “and” encompasses in this phrase. The phrase could be interpreted to mean that the oligonucleotide inhibitor is selected from an antisense RNA or DNA, siRNA or siDNA, miRNA, miRNA mimic, shRNA or DNA and also comprises a chimeric antisense DNA or RNA. The phrase could also be interpreted to mean that the oligonucleotide inhibitor is selected from the list consisting of an antisense RNA or DNA, siRNA or siDNA, miRNA, miRNA mimic, shRNA or DNA, and Chimeric Antisense DNA or RNA. For the purpose of compact prosecution, the last bullet point of Claim 29 is interpreted as “wherein the oligonucleotide inhibitor is an antisense RNA or DNA, siRNA or siDNA, miRNA, miRNA mimic, shRNA or DNA, or Chimeric Antisense DNA or RNA.”
Claim 42 recites “a composition comprising an effective amount of an inhibitor of claim 1, to reduce one or more symptoms of an autoimmune disease in a subject in need thereof, wherein the autoimmune disease is or includes CNS lupus.” Claim 42 recites an intended use of the composition (to reduce one or more symptoms of CNS lupus) (MPEP § 2111.02.II). The recited intended use does result in a structural difference in the composition, specifically the effective amount of the inhibitor. It is unclear what amount of inhibitor the composition needs to comprise to effectively reduce the symptoms of CNS lupus. Would a composition comprising 20 grams of inhibitor be encompassed by Claim 42? Would a composition comprising 200 µM of inhibitor be encompassed by Claim 42? Therefore, the recited intended use results in an indefinite claim limitation for the composition comprising an effective amount of an inhibitor.
Note, Claim 1 is interpreted wherein the autoimmune disease is CNS lupus. “An inhibitor of a nucleoside transporter” as recited in Claims 1 and 18 is a term understood in the art prior to the time of filing as evidenced by Rehan et al. SLAS Discov. Sep 2019 (Fig. 2 and Table 1). “Variants” in Claim 25 is not indefinite because the specification defines “variants” wherein the antibody can be composed of or include an antibody fragment or fusion protein including an amino acid sequence of a variable heavy chain and/or variable light chain that is at least 45% identical to the amino acid sequence of the variable and/or light chain of 3E10 or 5C6 or a humanized form thereof (page 76, lines 28-34). “Purine nucleoside analogue” in Claim 29 is not indefinite because purine nucleoside analogues are a class of drugs known in the art prior to the time of filing as evidenced by Robak et al. Curr Med Chem. 2006 (abstract and introduction).
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.
Claims 32-33 are 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 31 recites wherein the inhibitor is dipyridamole or a pharmaceutically acceptable salt thereof. Claims 32-33 depend on Claim 31, but recite wherein the inhibitor is a dipyridamole analogue or pharmaceutically acceptable salt thereof which results in a broader genus of inhibitor structures. The genus of dipyridamole analogues is broader than dipyridamole which has one defined structure. 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.
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 1-3, 7-9, 17-21, 25, 28-29, 31-33, and 41-42 are 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 claims contain 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.
Claim 1 is directed to a method of treating CNS lupus by administering an inhibitor of a nucleoside transporter which encompasses a genus of possible inhibitors that comprise any structure as long as they functionally inhibit any type of nucleoside transporter. Claim 18 is directed to a method of treating CNS lupus by administering an inhibitor comprising dipyridamole, an isomer thereof, or a pharmaceutically active analogue thereof which encompasses a genus of dipyridamole analogues that can comprise any structure as long as dipyridamole activity is maintained. The specification defines treating as the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder wherein preventative treatment is directed to inhibiting the development of the disease (page 13, lines 17-31). Therefore, “treating” is interpreted as both therapeutic treatment and prophylactic treatment.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. In order to provide adequate written description and evidence of possession of this claimed method, the specification must provide sufficient distinguishing identifying characteristics of the method.
The specification teaches that a cell penetrating antibody (h3E10 di-scFv) suppresses tumor growth and prolongs survival in a mouse model of triple negative breast cancer (TNBC) brain metastases (page 105, lines 18-24). The specification further teaches that h3E10 di-scFv crosses the blood-brain barrier via the nucleoside transporter ENT2, and dipyridamole can block ENT2 and suppress uptake of h3E10 di-scFv into mice brain tumors (pages 106-109). None of the working examples describe therapeutic treatment or prophylactic treatment of CNS lupus with any type of nucleoside transporter inhibitor.
Therefore, claims 1-3, 7-9, 17-21, 25, 28-29, 31-33, and 41-42 are rejected for insufficient written description.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1-3, 7-9, 17-21, 25, 28-29, 31-33, and 41-42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
MPEP § 2164.01(a) states that there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure
does not satisfy the enablement requirement and whether any necessary experimentation is
“undue”. These factors include, but are not limited to:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention:
The nature of the invention is complex, encompassing a method of treating CNS lupus by administering an inhibitor of a nucleoside transporter which encompasses a genus of possible inhibitors that comprise any structure as long as they functionally inhibit any type of nucleoside transporter. Claim 18 is directed to a method of treating CNS lupus by administering an inhibitor comprising dipyridamole, an isomer thereof, or a pharmaceutically active analogue thereof which encompasses a genus of dipyridamole analogues that can comprise any structure as long as dipyridamole activity is maintained. The specification defines treating as the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder wherein preventative treatment is directed to inhibiting the development of the disease (page 13, lines 17-31). Therefore, “treating” is interpreted as both therapeutic treatment and prophylactic treatment.
When analyzing enablement, the claims are analyzed with respect to the teachings of the specification and are to be "given their broadest reasonable interpretation consistent with the specification." See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
The state of the prior art and level of predictability in the art:
The level of predictability in the art depends, most importantly, on whether the claimed invention can be practiced by one of ordinary skill in the art. Kyttaris et al. Arthritis Rheum. 2011 teaches that dipyridamole can block cytokine production and block T cell mediated help to B cells in lupus mouse models (discussion last paragraph). Kyttaris concludes that dipyridamole should be evaluated as an addition to standard treatment in a human clinical trial of systemic lupus erythematosus (SLE) (discussion last paragraph).
However, Liu et al. Front Cell Dev Biol. 2022 teaches that neuropsychiatric systemic lupus erythematosus (NPSLE) is a devastating complication of SLE that involves the nervous system and produces neurological or psychiatric symptoms with a poor prognosis and high mortality (introduction paragraph 1). Note, CNS lupus is a species of NPSLE that specifically affects the brain or spinal cord. Liu teaches that the pathogenic processes that lead to neurological damage in SLE patients are largely unknown (section 2.2), even after the effective filing date of the instant invention. The diversity of neuropsychiatric symptoms in patients with NPSLE and the limited understanding of its complex pathogenesis have limited the development of targeted therapies (section 2.3). Several biological agents have been tried for the treatment of SLE with some clinical efficacy, but only belimumab has been approved by the U.S. Food and Drug Administration for the treatment of SLE; however, NPSLE is not an approved indication for belimumab and it has not been assessed in the management of central nervous system symptoms (section 2.3). This teaching demonstrates that therapies known to be effective in treating SLE are not guaranteed to be effective in CNS lupus. Liu teaches that, even after the effective filing date of the instant invention, the pathogenesis of CNS lupus was not understood and very few therapies are known to be effective in this disease setting.
The art teaches the important distinction between CNS lupus and SLE as well as the unpredictability and/or inability to therapeutically treat or prophylactically treat CNS lupus by administering inhibitors of nucleoside transporters. There is no support in the Applicant’s disclosure leading one of ordinary skill to overcome the lack of predictability in treating or preventing CNS lupus by administering inhibitors of nucleoside transporters.
Level of skill in the art:
The level of skill would be high encompassing neuroscience, immunology, molecular biology, etc.
Amount of direction provided by inventor and the existence of working examples:
The specification teaches no working examples of therapeutic treatment or prophylactic treatment of CNS lupus with any type of nucleoside transporter inhibitor. The specification only teaches examples pertaining to mouse models of triple negative breast cancer (TNBC) brain metastases (page 105, lines 18-24).
Because none of the working examples describe treatment or prevention of CNS lupus by administering an inhibitor of a nucleoside transporter, a person having ordinary skill in the art would have to make a substantial inventive contribution in order practice the claims as there is no guidance within the disclosure as filed pertaining to this embodiment.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
In light of the unpredictability surrounding the claimed subject matter, the breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to practice the presently claimed invention would be unable to do so without engaging in an unknown quantity of experimentation. Given that the nature of the claims is in vivo treatment, a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials or in animal models, that are predictive of CNS lupus treatment and prevention by administering a representative number of nucleoside transporter inhibitors to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the treatment with a reasonable expectation of success.
The instant specification does not enable the invention to therapeutically treat and prophylactically treat CNS lupus by administering any type of nucleoside transporter inhibitor.
Double Patenting
Note, no provisional double patenting rejection is made in view of U.S. Application 16/967109. The copending claims are directed to a method of treating lupus by administering an importin pathway inhibitor. An importin pathway inhibitor is distinct from the instant nucleoside transporter inhibitors, because the importin pathway is used in transporting large proteins into the cell nucleus and nucleoside transporters are membrane proteins that facilitate the movement of small nucleosides across cell membranes.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/STACEY N MACFARLANE/Examiner, Art Unit 1675