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 .
Application Status
Claims 1-18 were previously pending.
A Requirement for Restriction/Election office action was mailed 16 March 2026 whereby Applicant was required to: elect Invention 1 (Group I, claims 1-17) or Invention 2 (Group II, claim 18); and elect a species of the second adjuvant complex, in which the active site of the second adjuvant and an immune cell receptor are connected via a cleavable linker.
Applicant's election with traverse of Group I, claims 1-17, in the reply filed on 06 May 2026 is acknowledged. The traversal is on the ground(s) that the composition (Group I, claims 1-17) and method (Group II, claim 18) are linked by “the same single general inventive concept and should be regarded as constituting one invention” (Remarks, p. 2). This is not found persuasive because, as previously set forth, this common feature does not constitute a special technical feature defining a contribution over prior art references Salem (of record) and Coffman (of record), or lacks unity a posteriori. Applicant did not specifically address this matter of the special technical feature’s contribution over the cited prior art and therefore, the requirement is still deemed proper and is therefore made FINAL.
Applicant has elected the following species in their 06 May 2026 reply with traverse, and argues “the second adjuvant, linker, and immune cell are not separate species that independently destroy unity, but rather interrelated variables for implanting one common kinetic control mechanism” (Remarks, p. 3):
A toll-like receptor agonist as the specific second adjuvant;
A disulfide bond as the specific cleavable linker; and
A dendritic cell as the specific immune cell.
Claims 1-17 read on the elected species.
However, after further search and consideration, the species election requirement as indicated in the 16 March 2026 office action is withdrawn.
Therefore, claims 1-18 are currently pending. Claim 18 is withdrawn from consideration. Claims 1-17 are under examination.
Priority
Acknowledgement is made for the following priority:
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Information Disclosure Statement (IDS)
The IDSs (3) filed on 10 May 2023, 31 May 2024, and 22 April 2025 have been considered by the examiner. Signed copies are enclosed.
Applicant is reminded of their duty to disclose to the Office all information known to the person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section.”
Claim Objections
Claims 1-17 are objected to for the following informalities: the claims contain several grammatical errors. It would be remedial to amend the claims to comport with standard grammatical and/or linguistic conventions.
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.
Claims 1-17 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 following demonstrate significant ambiguity in the claims, so much so that one of ordinary skill in the art could not determine the metes and bounds of the claims.
Claim 1 is rejected under 35 U.S.C. 112(b) for the following reasons:
Claim 1 recites, “two or more types of adjuvants…” This phrase creates ambiguity insofar as determining the metes and bounds of the claim. Would two molecules acting at different receptors but belonging to the same chemical class constitute different types of adjuvants? The specification is silent regard what physical property would meet the threshold of types of adjuvants.
Claim 1 recites, “…a second adjuvant is a complex in which a cleavable linker binds to its active site, sequentially binds to an immune cell receptor to induce a second immune response.” The phrase ‘sequentially binds’ creates ambiguity as it is unclear what sequentially binds to the immune cell receptor. Is it the cleavable linker, the second adjuvant, the second adjuvant complex, or the second adjuvant after cleavage of the linker? The grammatically correct way to interpret this phrase would be the subjects immediately preceding ‘sequentially binds,’ which could be either the cleavable linker or the second adjuvant complex. The phrase ‘its active site’ is grammatically vague. Additionally, some claimed adjuvants, such as lipids, do not have a conventionally recognized singular active site, further adding to the vagueness of this phrase.
Claims 2-17 are included in this rejection for their dependency on, and including every limitation of, instant claim 1 and for failing to cure the defects.
Claim 2 is rejected under 35 U.S.C. 112(b) for the following reasons:
Claim 2 recites, “[t]he adjuvant ensemble composition of claim 1, wherein the kinetic action appears in such a manner…” This phrase ‘appears in such a manner’ does not provide a clear structural or functional limitation and therefore, creates ambiguity. Furthermore, the claim as a whole lacks antecedent basis as ‘kinetic action’ is not recited in claim 1 (note: the functional language contained in the preamble of claim 1 does not constitute antecedent basis).
Claim 2 recites, “…and then the cleavable linker blocking the active site is cleaved within 2 to 12 hours…” This phrase is ambiguous because neither the claim nor the specification defines the starting point for the 2- to 12-hour period. Is the starting point 2 to 12 hours after formulation, administration, contact with an immune cell, initiation of the first immune response, or another event? The specification seems to imply the starting point is 2 to 12 hours after administration into the body (see Specification, p. 13), however this interpretation cannot be read into the claim as it requires an active step absent from the claim.
Claim 2 recites, “…the activity of the immune activating material…” This phrase lacks antecedent basis as ‘immune activating material’ is not previously recited. Applicant is encouraged to review the following USPTO guidance on claim drafting: https://www.uspto.gov/sites/default/files/documents/Claim%20drafting.pdf
(The first time a limitation is introduced, applicant MUST introduce it with either ‘a’ or ‘an,’ while subsequent references to the already introduced limitation are made by either ‘said’ or ‘the.’)
Claim 2 recites, “the activity of the immune activating material is temporally delayed.” The claim does not specify what the activity is delayed relative to and is therefore ambiguous.
Claim 3 is rejected under 35 U.S.C. 112(b) for the following reasons:
Claim 3 recites, “wherein the cleavable linker comprises any one or more bonds selected from…” a group comprising hydrazine or azide. Hydrazine ordinarily identifies a compound or a functional moiety, not a bond. Similarly, azide ordinarily identifies a functional group, not a bond. It is therefore unclear whether claim 3 requires a linker containing the listed chemical moiety, a linker cleavable at a bond associated with that moiety, or a bond formally named in the listed terms (excluding those terms not representative of a bond).
Claim 5 is rejected under 35 U.S.C. 112(b) for the following reasons:
Claim 5 recites, “wherein the cleavable linker is cleaved at the chemical bond of a binding site…” First, it is unclear what ‘binding site’ references as there are two binding sites recited in claim 1 as it pertains to the second adjuvant. Second, ‘the chemical bond’ is claimed in claim 5 as if it has already been introduced in the claim from which it depends (claim 1). However, ‘chemical bond’ is not recited in claim 1 and therefore, this limitation lacks antecedent basis.
Claim 6 is rejected under 35 U.S.C. 112(b) for the following reasons:
Claim 6 recites, “[t]he adjuvant ensemble composition of claim 1, wherein any one or more materials [sic] selected from…” Claim 1 does not recite any materials specifically, so it is unclear if ‘materials’ reference the cleavable linker, the first antigen, the second antigen, both antigens, or an additional material. Therefore, there is lack of antecedent for this limitation in claim 6.
Claim 8 is rejected under 35 U.S.C. 112(b) for the following reasons:
Claim 8 recites, “[t]he adjuvant ensemble composition of claim 7, wherein the drug delivery system further comprises a first adjuvant.” Introducing ‘a’ first adjuvant indicates this is the first introduction of ‘first adjuvant’ in the claims. Therefore, it is unclear if first adjuvant references the first adjuvant of claim 1, or an entirely different adjuvant.
Claim 9 is rejected under 35 U.S.C. 112(b) for the following reasons:
Claim 9 recites, “…wherein the drug delivery system further comprises a ligand that is able to react with a receptor present on the surface of immune cells or in an endosome or cytosol.” The phrase ‘react with’ is unclear in this context and the specification does not provide further clarification. Does this phrase intend to limit the ligand-receptor interaction to chemical reactions as implied by ‘react with’? Or does it pertain to interactions such as specific binding, activation, inhibition, or association?
Claim 10 is rejected under 35 U.S.C. 112(b) for the following reasons:
Claim 10 recites, “wherein the drug delivery system further comprises any one or more immune activating materials selected from the group consisting of….a cytosolic DNA sensor (CDS ligand)…” A cytosolic DNA sensor is a receptor, not a ligand. It is therefore unclear if the limitation within the parenthesis is meant as an optional limitation, to further clarify the cytosolic DNA sensor, or is a limitation in itself. Of note to Applicant: that which is claimed in parenthesis is not a limitation of the metes and bounds of the claim.
Claim 12 is rejected under 35 U.S.C. 112(b) for the following reasons:
Claim 2 recites, “wherein the first adjuvant is any one or more immune activating materials selected from the group consisting of….a cytosolic DNA sensor (CDS ligand)…” A cytosolic DNA sensor is a receptor, not a ligand. It is therefore unclear if the limitation within the parenthesis is meant as an optional limitation, to further clarify the cytosolic DNA sensor, or is a limitation in itself. Of note to Applicant: that which is claimed in parenthesis is not a limitation of the metes and bounds of the claim.
Claim 13 is rejected under 35 U.S.C. 112(b) for the following reasons:
Claim 13 recites, “wherein the immune cells are any one or more selected from the group consisting of antigen-presenting cells (dendritic cells or macrophages)…” Since there are other antigen-presenting cell (APC) types in addition to dendritic cells or macrophages, it is unclear whether the limitation contained within the parenthesis is further meant to limit the preceding term, provide examples of APCs, or serve as a limitation on its own. Of note to Applicant: that which is claimed in parenthesis is not a limitation of the metes and bounds of the claim.\
Claim 16 is rejected under 35 U.S.C. 112(b) for the following reasons:
Claim 16 recites, “wherein the antigen is one or more selected from the group consisting of…a gene” A gene is not an antigen, but certain gene products can act as antigens. Therefore, this limitation creates ambiguity within the claim.
Claim Rejections - 35 USC § 112(a) – Written Description
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 1-7, 9-10, 12, and 14-17 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.
Claims 1-7, 9-10, 12, and 14-17 are drawn to a set of kinetically controllable immune modulator compositions, said compositions comprising a first adjuvant capable of binding to an immune cell receptor to induce a first immune response, and a second adjuvant-containing complex bound to any cleavable linker that further binds to an immune cell receptor to induce a second immune response. The rejected claims are thus drawn to a genus of compounds solely defined by their functional ability.
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 a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
Although the disclosure provides schematic reaction pathways and synthetic outlines for a limited set of complexes comprising various adjuvants, cleavable-linker types, and TLR7/8 agonists, these schematics are prophetic and do not establish possession of the broad functional genus recited in the claims. There are no comparable working embodiments for saponin adjuvants, alum, STING agonist, NOD agonists, inflammasome inducers, antiviral peptides, pathogen-cell-wall components, protein adjuvants, oligonucleotide adjuvants, lipid adjuvants generally, a combination of the aforementioned adjuvants, or derivatives of the aforementioned adjuvants. These substances have materially different structures, receptor interactions, active regions, cellular locations, and masking chemistries. A skilled artisan would not necessarily understand from the disclosed TLR7/8 species what structural features define the entire claimed genus of adjuvant ensemble compositions as the claims encompass a vastly larger and more diverse genus, including (i) “one or more” immune activating materials, combinations thereof, and derivatives thereof; (ii) six structurally unrelated drug delivery systems; and (iii) an exceptionally broad set of cleavable linkers spanning mechanisms as diverse as pH-sensitive hydrolysis, enzymatic cleavage, thermal elimination, with numerous chemical bond types including esters, peptides, disulfides, and others. These systems differ dramatically in chemical compatibility, cleavage behavior, linker stability, conjugation feasibility, and biological function. In the unpredictable arts of immunomodulatory conjugates, high-level schematics and lists of hypothetical combinations do not substitute for evidence of possession or enablement of the full claim scope.
The disclosure provides support for a relative narrow genus centered on cholesterol-toll-like receptor agonist complexes including polyinosinic-polycytidylic acid (poly I:C) as a toll-like receptor 3 agonist, Lipopolysaccharide (LPS) as a toll-like receptor 4 agonist, and resiquimod (R-848) as a toll-like receptor 7 or 8 agonist (Example 14). The specification further discloses saponin immune modulators at Example 11.3 and delivery of immunogenic compositions via nanoparticles at Example 11. No description is provided of any kinetically controllable immune modulators bound to any cleavable linker other than the limited subset of immune modulators (i.e. toll-like receptor agonists) bound to cholesterol set forth above. Furthermore, no additional working example of delivery systems (as recited at claim 7) other than nanoliposome and polymeric nanoparticle is provided. Thus, it is impossible for one of ordinary skill in the art to extrapolate from the few examples described herein those kinetically acting immunogenic compositions that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of immunogenic compositions that encompass any kinetically controllable immune modulator bound to any cleavable linker that induces two separate immune responses.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1-7, 9-10, 12, and 14-17.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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 14-17 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 a kinetically active ensemble composition containing two adjuvants, does not reasonably provide enablement for the treatment or prevention of cancer, metabolic syndrome, an autoimmune disease, or a rare disease. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: 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 the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claims 14 is drawn to a composition for the prevention or treatment of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease. Claims 15-17 depend from claim 14 and therefore incorporate the preventive use limitation. Claim 15 further encompasses treatment or preventive compositions comprising any antigen, chemotherapeutic agent, or immune-checkpoint inhibitor. The nature of the invention is complex in that one must be able to prevent or treat any of the claimed diseases, all of which have different causes and different mechanisms of pathogenesis, with the immunogenic composition disclosed therein. Of note: each of these intended use claims depend from claim 1, which only requires a composition containing two adjuvants.
Breadth of the claims: The claims broadly encompass the administration of compositions defined solely or primarily by function (as set forth above), where the compositions must be effective to prevent or treat any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. In claim 1, for instance, applicant has only claimed two adjuvants used in the treatment or prevention of diseases spanning neoplastic disease, infectious disease, autoimmune disease, metabolic disease, and a rare disease spanning any genetic, metabolic, neurological, autoimmune, infectious, neoplastic, degenerative, or developmental disease.
Guidance of the specification and existence of working examples:
The specification broadly defines the following:
Infectious Disease: the “generic term for diseases induced by infection caused by a heterogenous organism, such as a virus, a bacterium, or a fungus” (p. 22, lines 21-23);
Cancer: broadly encompasses the majority of known cancers (p. 23, lines 1-24);
Metabolic Syndrome: “a combination of three or more among five risk factors (high blood pressure, hyperglycemia, hypertriglyceridemia, low HDL cholesterol, and abdominal obesity) that increase heath problems” over a broad spectrum of known metabolic disorders (p. 24, lines 1-7);
Autoimmune Disease: “the generic term for diseases caused by pathological responses to an autoantigen and includes systemic autoimmune diseases…” (p. 24, lines 8-12);
Rare Disease: “the generic term for all diseases affecting only a small proportion of the population, which are usually hereditary, and generally refers to a disease that is difficult to diagnose due to its very low incidence or prevalence and has no proper treatment” (p. 24, lines 13-25 and p. 25, lines 1-2);
Prevention: all actions that inhibit diseases or delay the onset thereof (p. 22, lines 10-13); and
Treatment: all actions that are involved in improving or beneficially changing symptoms of infectious diseases, cancer, metabolic syndrome, autoimmune diseases, or rare diseases (p. 22, lines 14-17).
While the specification broadly envisions prevention or treatment of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease by administering an adjuvant ensemble composition, it does not specifically teach prevention or treatment of the claimed diseases by administering two adjuvants with sufficient specificity. As set forth above, the specification describes proof-of-principle kinetically acting adjuvant ensemble compositions comprising cholesterol-toll-like receptor agonist complexes, wherein said toll-like receptor agonists include polyinosinic-polycytidylic acid (poly I:C) as a toll-like receptor 3 agonist, Lipopolysaccharide (LPS) as a toll-like receptor 4 agonist, and resiquimod (R-848) as a toll-like receptor 7 or 8 agonist (Example 14). The specification further discloses saponin immune modulators at Example 11.3 and delivery of immunogenic compositions via nanoparticle at Example 11. The specification provides confirmation of antitumor efficacy using a species of the claimed composition, relating principally to a particular nanoadjuvant containing poly(I:C) and a cleavably masked TLR7/8 agonist in mouse tumor models. No description is provided of prevention or treatment of disease, including an infectious disease, cancer, metabolic syndrome, an autoimmune disease, or a rare disease, as is instantly claimed using only two adjuvants.
In particular, the specification does not adequately identify the following:
Disease-specific preventive compositions;
Defined at-risk populations susceptible to the claimed diseases;
The timing of administration prior to disease onset to elicit the prophylactic effects;
Prophylactic doses and dosing schedules including the duration of treatment;
Preventive efficacy endpoints for each of the claimed diseases;
Minimum reduction in disease incidence regarded as effective;
Appropriate antigens for the broad genus of diseases; or
A general mechanism by which the disclosed adjuvant ensemble would prevent all claimed diseases.
Predictability and state of the art: The claims explicitly encompass preventing or treating any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease in a subject. Looking to the prior art for guidance, a search of the prior art did not identify any methods which utilized a kinetically controlled immunogenic composition comprising two or more immune-activating adjuvants which could effectively prevent or treat any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease in a subject. In fact, no prior art was identified which used only adjuvants (as recited in claim 1) to treat active diseases (as recited in claim 14, which depends from claim 1). Furthermore, the specification also does not provide any working example demonstrating prevention of any one of the claimed diseases in a subject. Therefore, given the lack of knowledge present in the prior art and the lack of guidance provided in the specification with respect to preventing or treating any one or more claimed diseases, further experimentation would be required. Considering that the additional experimentation would require de novo experimentation without a guarantee of success, and further considering that any positive results (i.e., successful prevention of the claimed diseases in a subject) would amount to a significant advancement in the state of the art, the additional experimentation required is considered undue.
In In re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case here where there is a relatively incomplete understanding in the biotechnological field involved, as described above, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims.
Therefore, it is appropriate to reject the claims under 35 USC 112(a) for not being enabled for prevention or treatment of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease.
While design of therapeutic vaccines and experimentation thereof are both within the realm of knowledge by those of ordinary skill in the art, the breadth of diseases encompassed by the instant claim set would require substantial and repeated experimentation for numerous, disparate diseases such that the additional experimentation required is considered undue, particularly in the absence of any guidance provided in the instant specification. Furthermore, the claimed composition of claim 1 only requires two adjuvants. While other claims attempt to add more specificity to the adjuvant composition (e.g., claims 15 and 16 broadly claim additional genus components of the composition such as an antigen), the use claim 14 requiring treatment and prevention of the claimed diseases depends from claim 1. Under its broadest reasonable interpretation, claim 1 only requires a composition of two adjuvants, without the presence of an antigen, used to prevent or treat a wide array of diseases, which would be a novel and groundbreaking discovery in the field of vaccines.
Amount of experimentation necessary: As set forth above, the quantity of experimentation required to make and use the full scope of the claimed invention would be large. While the required experimentation is theoretically within the realm of experimentation by those of ordinary skill in the art, the breadth of diseases encompassed by the instant claim set would require substantial and repeated experimentation for numerous, disparate diseases such that the additional experimentation required is considered undue, particularly in the absence of any guidance provided in the instant specification.
Other than contemplating the utility of the claimed immunogenic composition in preventing or treating any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease, the specification does not disclose how to design or use any of kinetically acting compositions required to treat a subject in need thereof. As clearly stated in Genentech Inc. v. Novo Nordisk NS (CAFC) 42 USPQ2d 1001: “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. Tossing out the mere germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” See also Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966), stating in the context of the utility requirement that “a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.” Applicant cannot rely on the knowledge of one skilled in the art to supply information on the novel aspects of the claimed invention, to which the instantly filed disclosure is largely silent, as set forth above.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 14-17 are not considered to be enabled by the instant disclosure regarding the treatment and prevention of claimed diseases.
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 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over Salem (cited in previous office action as US 2014/0127253; published 08 May 2014) in view of Coffman (cited in previous office action as US PGPub No. 2019/0151462; published 23 May 2019) as evidenced by Kaczanowska (“TLR agonists: our best frenemy in cancer immunotherapy,” published: June 2013).
Salem discloses cleavable conjugates of TLR7/8 agonists containing a conjugation linker, a cleavable linker, and a self-eliminating linker for stimulating an effective immune response and for treatment of cancer (abstract).
Regarding claim 1, Salem teaches a three-component composition comprising a tumor antigen, a first immune adjuvant, and a second immune adjuvant (claim 1). Salem further teaches two or more adjuvants co-delivered in a composition with an antigen advantageously exhibits a synergistic anti-tumor effect and will generate a stronger immunostimulatory response in comparison to the delivery of the antigen alone ([0051]). Salem further demonstrates co-delivery of ovalbumin (example antigen), poly(I:C) (example TLR-3 ligand adjuvant), and CpG (example TLR-9 ligand adjuvant) co-loaded on a PLGA microparticle ([0094-0095]). Salem teaches each of these adjuvants induce a separate and distinct immune response, wherein poly(I:C)-mediated TLR-3 activation is described as promoting dendric cell maturation, NK cell responses, and antigen-specific cytotoxic activity, while CpG-mediated TLR-9 activation produces direct and indirect immune effects involving dendritic cells, NK cells, and T cells ([0010-0011]).
While Salem does not expressly teach that its second adjuvant is initially maintained in an inactive state by a cleavable linker attached at a functionally active portion of the adjuvant and subsequently activated following the linker cleavage, this limitation is made obvious in view of Coffman.
Coffman discloses that the subject matter taught therein relates to methods for preparation of a therapeutic agent or vaccine adjuvant ([0158] and [0401]) capable of targeting specific tissues, thereby reducing unwanted systemic immune activation ([0007]). Coffman specifically discloses adjuvants comprising conjugates of TLR7/8 agonists to stimulate an immune response ([0158]). Coffman discloses a TLR7/8 agonist moiety covalently connected through a self-eliminating linker and a cleavable linker, whereby the TLR7/8 adjuvant is held in a relatively inactive state until the linker is cleaved ([0376], [0400]).
A person of ordinary skill, before the effective filing date of the claimed invention, would have been motivated to make the modification to Salem in order to retain Salem’s advantageous combined stimulation of two different innate immune receptors; spatially and temporally control the activity of the second adjuvant; reduce systemic or off-target inflammatory activity associated with an active TLR agonist; release the active second agonist following exposure to the intended biological cleavage environment; and provide initial immune stimulation by the first adjuvant followed by later immune stimulation from the cleaved second adjuvant.
Both references pertain to control of TLR agonist activity. Salem recognizes a sequential adjuvant release where the antigen and adjuvant are encapsulated in a nanoparticle and the other antigen is adsorbed on the surface of the nanoparticle to protect the antigen and adjuvant from rapid degradation and clearance and achieve a favorable release profile ([0052-0053]) while Coffman expressly addresses control of TLR agonist activity through reversible chemical conjugation and localized release ([0006]). The references therefore address compatible problems in the same field of immune-adjuvant delivery.
A person of ordinary skill would have reasonable expectation of success in the modification because Salem demonstrates successful co-delivery of different TLR agonist adjuvants in biodegradable particles while Coffman expressly teaches its conjugated TLR7/8 agonists have reduced activity before cleavage and greater activity following the release of the unconjugated agonist. Incorporating the Coffman conjugate as Salem’s second adjuvant would predictably provide an initially available first TLR stimulus and a later second TLR stimulus following linker cleavage. Accordingly, claim 1 would have been obvious over Salem in view of Coffman.
Regarding claim 2, Figure 4 of Coffman illustrates the kinetic control of the immune modulator (IMDQ-a TLR7/8 agonist), wherein said immune modulator is released over several hours (see also paragraph [0657]). The time course of IMDQ release depicted in Figure 4 of Coffman reads on the instantly claimed range of 2 to 12 hours after the linker is cleaved.
Regarding claim 3, Coffman discloses the cleavable linker is selected from a peptide-based or a disulfide linker ([0382]).
Regarding claim 4, Coffman discloses the cleavable linkers taught therein may comprise ethylene oxide or ethylene glycol species at the N-terminus ([0146] and [0671]; claims 1, 77, and 86).
Regarding claim 5, Coffman discloses the cleavable linkers taught therein may be cleaved by a proteolytic enzyme such as cathepsin B ([0383]).
Regarding claim 6, Coffman discloses the cleavable linkers taught therein may be peptide-based comprising amino acid residues and amino acid motifs ([0383] and [0384]).
Therefore, Coffman expressly teaches each of the claimed limitations in instant claims 1-6 as it pertains to the cleavable linker.
Regarding claims 7 and 8, Salem discloses the two adjuvants and antigen taught therein are incorporated into nanoparticles ([0131]) or emulsions ([0061]).
Regarding claim 9, Salem discloses poly(I:C), a TLR-3 ligand ([0011]) as a component of the composition taught therein. While Salem does not specifically disclose the TLR3 agonist interacts with a specific cellular location, it is known in the art that TLR3 localizes to endosomes (Kaczanowska, Table 1).
Regarding claim 10, Salem discloses the immune-activating material is a toll-like receptor agonist ([0009] and [0011]).
Regarding claims 11 and 12, Salem discloses the two adjuvants are CpG and poly(I:C), two toll-like receptor agonists.
Regarding claim 13, Salem discloses CpG is recognized by TLR9, which is expressed only in B cells and dendritic cells ([0009]).
Regarding claim 14, Salem discloses the three-component composition of the invention taught therein is used in tumor therapy ([0053]) and used for the treatment of cancer based on the administration of the composition ([0032]).
Regarding claim 15, Salem discloses one of the components of the composition taught therein is an antigen ([0028]).
Regarding claim 16, Salem discloses the antigen component of the invention is a tumor-specific antigen such as prostate PSA ([0063]), a glycoprotein.
Regarding claim 17, Salem discloses the composition taught therein is capably of tumor inhibition ([0024]).
As previously discussed, given that Salem discloses an immunogenic composition comprising an antigen and two adjuvants; and that Coffman discloses cleavable linkers relevant to immunogenic compositions that facilitate tissue-specific targeting and release of said immune modulator over several hours following administration, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to connect the antigen and TLR agonist adjuvant in Salem with the cleavable linker attached to an immune modulator (i.e. a TLR7/8 agonist) disclosed in Coffman and delivered via nanoliposomes or nanoparticles as disclosed in Salem to predictably produce an immunogenic composition that facilitates tissue-specific targeting and reduces systemic immune activation by controlling the release of the immune modulator, thereby treating diseases such as cancer. One would have been motivated to make such a modification in order to receive the expected benefit of reducing unwanted systemic immune activation.
Conclusion
Claims 1-17 are objected to. Claims 1-17 are rejected. No claim is allowed.
Communication
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/JULIA A. ROSSI/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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