DETAILED ACTION
Claims 1, 3-5, 10-17, 27-32, and 36-39, submitted 14 February 2023, are pending in the application. Claims 14-17, 27-32, and 36-39 have been withdrawn. Claims 1, 3-5, and 10-13 are subject to examination in the instant Office 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 of Group I, claims 1, 3-5, and 10-13, and the elected species of therapeutically active molecule of immunotherapy drug, wherein the immunotherapy drug is galactosyl ceramide, and the elected species of compound wherein Z = H, B = galactosyl ceramide, and X = OH in the reply filed on 30 September 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)).
Claims 14-17, 27-32, and 36-39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 30 September 2025.
Specification
The disclosure is objected to because of the following informalities: “glactosylceramide” is misspelled in paragraph 65. Applicant is asked to please amend the spec to read “galactosyl ceramide”.
Appropriate correction is required.
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, 3-5, and 10-13 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 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.
Claim 1 recites “…providing a composition comprising a conjugate of completely succinylated poly(lysine succinylated) polymer and a therapeutically active molecule…”, for which the specification does not provide adequate written description to convey that the inventors were in possession of the full scope of the claimed invention.
The Applicant has provided adequate written description for certain aspects of the instantly claimed invention. Applicant has provided guidance with respect to the method of delivery of a therapeutically active molecule to the brain and lymphatics of a patient using a conjugate of completely succinylated poly(lysine succinylated) polymer and a therapeutically active molecule. Specifically, when said therapeutically active molecule is the anti-parasitic drug, hydroxychloroquine, as detailed in Examples 3-4 found in paragraphs 124-127 of the instant specification, which teaches the synthesis of 10k and 25k hydroxychloroquine poly(L-lysine succinylated) prodrugs and Figure 15. The Applicant also provided guidance for the anti-cancer drug, breflate, as detailed in Examples 6-7 found in paragraphs 129-133 of the instant specification, which teaches the synthesis of breflate poly(L-lysine succinylated) prodrugs and the treatment of human melanoma cancer cells in a mouse model. The Applicant has also provided adequate written description in the form of exemplification of the structures of the poly(L-lysine succinylated) conjugates of PI-103 (paragraph 73), lamivudine (paragraph 76), emtricitabine (paragraph 78), and trehalose (paragraph 83). However, the Applicant did not provide experimental data for the aforementioned exemplified compounds.
The Applicant also fails to provide adequate written description for the elected species of compound conjugated to an immunotherapy drug, wherein that immunotherapy drug is galactosyl ceramide. Applicant failed to exemplify or teach experimental data regarding the use of the elected species wherein Z = H, B = galactosyl ceramide, and X = OH. In fact, the Applicant only makes mention of galactosyl ceramide 3 times, as a preferred embodiment in paragraph 64 of the instant specification, and in paragraph 65 where it makes note of examples of useful anti-cancer drugs and also teaches “other examples of suitable therapeutic compounds useful in the present invention may include…and galactosylceramide (as an immunomodulatory drug)”. As the previous statement appears to read as a prophetic statement, and in view of the lack of experimental data surrounding the elected species of the invention, the instantly claimed invention is not described in such a way as to reasonably convey to one skilled in the art that the inventor, at the time the application was filed, had possession of the instantly claimed invention.
Regarding the requirement for adequate written description, the Applicant is
directed to MPEP 2163 which states “An applicant shows that the inventor was in
possession of the claimed invention by describing the claimed invention with all of its
limitations using such descriptive means as words, structures, figures, diagrams, and
formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107
F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997)”. Based on the language of
the specification and absence of supporting material, the Examiner concludes that the
Applicant does not have possession of the claimed invention.
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, 3-5, and 10-13 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 the delivery of a therapeutically active molecule to the lymphatics of a patient, the method comprising the steps of: providing a composition comprising a conjugate of completely succinylated poly(lysine succinylated) polymer and a therapeutically active molecule, does not reasonably provide enablement for delivery of all therapeutically active molecules nor does it provide enablement for delivery of all therapeutically active molecules to the brain. 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.
Breadth of the Claims
Claim 1 recites the use of “a therapeutically active molecule”. Claim 1 is not drawn to any particular therapeutically active molecule and thus can be interpreted to encompass all therapeutically active molecules.
Applicant has defined a therapeutically active molecule as “a compound which can be used for diagnosis or treatment of a disease” which can be interpreted to include all known therapeutically active molecules. See instant specification, paragraph 53.
Claim 1 recites “the method of delivery of a therapeutically active molecule to the brain…”, for which the instant specification does not reasonably provide enablement for.
Nature of the Invention
The nature of the invention is within the pharmaceutical arts with regards to the delivery of a therapeutically active molecule to the brain or lymphatics of a patient.
State of the prior art
The state of the prior art is what one skilled in the art would have known, at the
time the application was filed, about the subject matter to which the claimed invention
pertains. The relative skill of those in the art refers to the skill of those in the art at the
time the application was filed. See MPEP 2164.05(b). See Pac. Bioscience of Cal., Inc. v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir.
2021).
The state of the prior art provides evidence for the degree of predictability in the
art and is related to the amount of direction or guidance needed in the specification as
filed to meet the enablement requirement. The state of the prior art is also related to the
need for working examples in the specification. See MPEP 2165.05(a).
The prior art teaches various methods of use for poly-L-lysine, for example, Zhu et al. ("Polylysine complexes and their biomedical applications." Engineered Regeneration 4.1 (2023): 20-27.) teaches applicability such as for cargo delivery, antibacterial coating, tissue sealing, biosensing, and bioimaging (pg. 20, Section “Introduction”, Right Col., 1st paragraph). However, Zhu also teaches wherein the inherent cationic property can cause issues due to the attendant cytotoxicity and rapid systemic elimination (pg. 25-26, Section “Conclusion and perspectives”, Right Col. and Left Col. bridging, 1st paragraph). Additionally, Zhu teaches that the electrostatic interaction usually leads to a high risk of cytotoxic and hemolytic effects, since the anionic membranes of mammalian cells and erythrocytes, make them potential objectives to be attacked by cationic PLLs and that the higher the molecular weight is, the more deleterious is for PLLs to lower the intracellular ATP levels, inducing acute energy crisis, cell dysfunction and eventually necrotic cell death (pg. 20, Section “Introduction”, Left Col., 2nd paragraph).
As taught by Zhu, compounds with larger molecular weight would appear to induce negative effects of the poly-L-lysine conjugate. It would follow then that there is significant uncertainty for the functional applicability of the polymer with all known therapeutically active molecules.
Further, the prior art teaches an identical Cy7.5-labeled poly(L-lysine succinylated) delivery vehicle wherein the compound was administered by tail vein injection and did not have a signal detection in the brain, pancreas, or muscle tissues collected (pg. 3801, Section “Biodistribution of Fluorescently Labeled PLS”, Right Col., 1st paragraph), as taught by Stevens et al. ("Application of a scavenger receptor A1-targeted polymeric prodrug platform for lymphatic drug delivery in HIV." Molecular pharmaceutics 17.10 (2020): 3794-3812.). Stevens also discloses that “even though brain microvessel endothelial cells have been shown to take up succinylated proteins via a scavenger receptor-dependent mechanism, we did not observe significant brain uptake in our imaging studies”.
Level of Skill in the Art
The person of ordinary skill in the art is a person who is presumed to have known
the relevant art at the relevant time. Factors that may be considered in determining the
level of ordinary skill in the art may include: (A) "type of problems encountered in the
art;" (B) "prior art solutions to those problems;" (C) "rapidity with which innovations are
made;" (D) "sophistication of the technology; and" (E) "educational level of active workers in the field. In a given case, every factor may not be present, and one or more
factors may predominate." In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121
(Fed. Cir. 1995); Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955,
962, 1 USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. V. Union Oil
Co., 713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983). See MPEP 2141.03 (I).
The invention described pertains to the medical or pharmaceutical arts. One of
ordinary skill would be trained in pharmacology, biochemistry, medicine, or a related art
field with a Ph. D or other advanced degree in these or other related fields.
Level of Predictability in the Art
The amount of guidance or direction needed to enable the invention is inversely
related to the amount of knowledge in the state of the art as well as the predictability of
the art. In re Fisher, 427, F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount
of guidance or direction” refers to that information in the application, as originally filed,
that teaches exactly how to make or use the invention. The more that is known in the
prior art about the nature of the invention, how to make, and how to use the invention,
and the more predictable the art is, the less information needs to be explicitly stated in
the specification. In contrast, if little is known in the prior art about the nature of the
invention and the art in unpredictable, the specification would need more detail as to
how to make and use the invention in order to be enabling. The scope of the required
enablement varies inversely with the degree of predictability involved, but even in
unpredictable art, a disclosure of every operable species is not required. A single
embodiment may provide broad enablement in cases involving predictable factors, such
as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA
1971). However, in applications directed to inventions in arts where the results are
unpredictable, the disclosure of a single species usually does not provide an adequate
basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA
1938). In cases involving unpredictable factors, such as most chemical reactions and
physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166
USPQ 18, 24 (CCPA 1970). See MPEP 2164.03. The applicant would need to provide
more objective evidence to support the enablement of the aforementioned claims to
contrast the unpredictability of the subject matter art.
There is unpredictability in the field of endeavor in regards to the currently
claimed method for the delivery of a therapeutically active molecule to the brain or lymphatics of a patient, the method comprising the steps of: providing a composition comprising a conjugate of completely succinylated poly(lysine succinylated) polymer and a therapeutically active molecule. There is unpredictability in the pharmaceutical arts with the practice of the delivery of all therapeutically active molecules with a single delivery vehicle. Further, there is significant uncertainty in the administration of all therapeutic active molecules to the brain of a patient as it’s known in the art that there are challenges with passage through the blood-brain barrier.
Amount of Direction Provided by the Inventor
The amount of direction provided by the inventor is correlated by the nature of
the unpredictability of the art. Given the context and scope of the claims mentioned
above, the inventor failed to provide the necessary amount of direction for one skilled in
the art to adequately use the invention across all suggested utility in the broadly stated
disease and disorders disclosed above. (See: Section (A) Breadth of the Claims).
The Applicant has provided guidance for the synthesis of 10k and 25k hydroxychloroquine poly(L-lysine succinylated) prodrugs and the synthesis of breflate poly(L-lysine succinylated) prodrugs and the treatment of human melanoma cancer cells in a mouse model as detailed above. The Applicant has also provided guidance in the form of exemplification of the structures of the poly(L-lysine succinylated) conjugates of PI-103 (paragraph 73), lamivudine (paragraph 76), emtricitabine (paragraph 78), and trehalose (paragraph 83). However, the Applicant did not provide experimental data for the aforementioned exemplified compounds.
Quantity of Experimentation Needed to Make or Use the Invention Based on the Content of the Disclosure
As previously stated, the amount of experimentation depends on the art, the
predictability of the art, and the direction provided by the inventor. For one skilled in the
art to practice the invention as disclosed, the artisan trying to practice Applicant’s
claimed invention would be required to undertake unduly burdensome activities
including:
Experimentation to demonstrate the application of the specifically elected succinylated poly(lysine succinylated) polymer bioconjugated to the galactosyl ceramide.
Experimentation to show dose and frequency of the specifically elected succinylated poly(lysine succinylated) polymer bioconjugated to the galactosyl ceramide.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JUSTIN CHRISTOPHER SANCHEZ whose telephone number is (703)756-5336. The examiner can normally be reached Monday -Friday (0730-1700).
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JUSTIN CHRISTOPHER SANCHEZ
Examiner
Art Unit 1622
/J.C.S./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622