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 .
Elections/Restrictions
Applicant’s election of claims 1, 3, 10, 12, 14, and 16-18 in the reply filed on May 19, 2026 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 2, 4-9, 11, 13, 15, 19, 21, 23-27, 29, 31-32, 39-46, 48-51, and 53-60 are canceled. Claims 20, 22, 28, 30, 33-38, 47, and 52 are withdrawn.
Claims 1, 3, 10, 12, 14, and 16-18 are examined herein.
Drawings
The drawings are objected to because:
The specification refers to blue and red traces in the drawings (pg. 5-7, 9-10, and 39) but the drawings are reproduced in black-and-white; therefore, referencing color traces is not informative.
Claim Objections
Claims 1 and 3 are objected to because of the following informalities:
Claim 1 recites “c) further comprising a targeting moiety or moieties; and/or”. Should be “c) further comprising a targeting moiety or moieties;” because “and/or” is entered after e).
Claim 3 recites the complement inhibitory protein is selected from those in Table 1. The proteins from Table 1 should be recited in the claim.
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, 10, 12, 14, and 16-18 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 a composition comprising: a) a therapeutic molecule, diagnostic molecule, molecular complex, or nanoparticle having a complement inhibitory protein attached thereto; or b) a therapeutic molecule, diagnostic molecule, molecular complex, or nanoparticle having a peptide or aptamer that binds a complement inhibitory protein attached thereto.
Claim 3 recites a) wherein the nanoparticle is a lipid nanoparticle or liposome; b) wherein the nanoparticle is a protein-coated nanoparticle or polymeric nanoparticle; c) further comprising a targeting moiety or moieties; d) wherein the complement inhibitory protein is selected from those in Table 1, or a functional variant or functional fragment thereof; e) wherein the aptamer has a sequence of SEQ ID NO: 5, or a sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions as compared to SEQ ID NO: 5.
Claim 12 recites the complement inhibitory protein is a variant that includes unnatural amino acids and/or is truncated.
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc) (MPEP §2163.03.V).
“[T]he disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." (MPEP § 2163.II.A).
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.") (MPEP § 2163).
Claim 1 is broadly drawn to any therapeutic molecule, diagnostic molecule, molecular complex, or nanoparticle having any complement inhibitory protein attached thereto (in a) and any peptide or aptamer that binds any complement inhibitory protein (in b). Claim 18 additionally recites any multimolecular complex.
The specification discloses a number of diagnostic and therapeutic agents (e.g., pg. 31, par. 3-4 and pg. 32, par. 1) but fails to establish “a reasonable structure-function correlation”. For example, disclosed nucleic acids (mRNA, miRNA, siRNA, or DNA), protein therapeutics, small molecule drugs, gene editing agents, and gene-silencing agents have very diverse structures and do not share similar structure-function correlation. Agents on page 32 (par. 1) are disclosed by their functions but not by their structures; for example, antifungal agents or nutritional agents.
The specification fails to disclose any molecular (claim 1) or multimolecular (claim 18) complex by structure.
Regarding the complement inhibitors, the specification discloses complement inhibitory proteins (Table 1) only by their function.
Regarding the peptides or aptamers that bind complement inhibitory proteins, the specification discloses two aptamers of SEQ ID NO:5 and 10 with affinity to factor H; two aptamers of SEQ ID NO:8 and 9 with affinity to C5aR1; three aptamers of SEQ ID NO:11-13 with affinity to C4BP; two aptamers of SEQ ID NO:14-15 with affinity to vitronectin. The potential diversity of the aptamer sequences is significant. Disclosed two or three sequences are insufficient as “representative of the full variety or scope of the genus,” or for the establishment of “a reasonable structure-function correlation.” Additionally, the specification fails to disclose any peptides that can bind complement inhibitory proteins.
Claim 3 is broadly drawn to: (a) a nanoparticle which is any lipid nanoparticle, liposome, protein-coated nanoparticle, or polymeric nanoparticle; (b) any targeting moiety or moieties; (c) any functional variant or functional fragment of the complement inhibitory proteins disclosed in Table 1; (d) any sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions as compared to SEQ ID NO: 5.
The specification fails to adequately reflect the structural diversity of the claimed genera of nanoparticles, lipid nanoparticles, liposomes, protein-coated nanoparticles, polymeric nanoparticles, and targeting moieties.
Additionally, the specification fails to disclose functional variants or functional fragments of the complement inhibitory proteins disclosed in Table 1. Table 1 lists only full-length wild type proteins without any variants or fragments.
Finally, the specification fails disclose any SEQ ID NO: 5 variant that is still capable of binding a complement inhibitory protein.
The art of protein structure-function relationship is unpredictable. There is no ready method to determine which variant or fragment will be able to perform the function of the full-length, wild type protein. Therefore, one of ordinary skill in the art will not be able to be able to determine with a reasonable degree of certainty which variant or fragment can be used in this invention.
Claim 12 is broadly drawn to any complement inhibitory protein comprising any number of unnatural amino acids and/or any complement inhibitory protein truncated by unspecified number of amino acids.
The specification fails to provide examples of any complement inhibitory protein having unnatural amino acids and/or truncations while still preserving their complement inhibitory functions. The only disclosed information regarding unnatural amino acids is “A variant may also include a non-natural amino acid” (pg. 19, par. 1).
Regarding truncated variants, the specification provides only a general definition of fragments “"Fragments" of proteins or peptides in the context of the present invention may, typically, comprise a sequence of a protein or peptide as defined herein, which is, with regard to its amino acid sequence (or its encoded nucleic acid molecule), N-terminally and/or C-terminally truncated compared to the amino acid sequence of the original (native) protein (or its encoded nucleic acid molecule). Such truncation may thus occur either on the amino acid level or correspondingly on the nucleic acid level” (pg. 17, par. 4). Prior art is silent on functionally active truncated variants of any existing complement inhibitory protein.
The art of protein modifications is highly unpredictable and one of ordinary skill in the art cannot readily predict the effect of unnatural amino acids and/or truncations of complement inhibitory proteins on their functionality.
Therefore, claims 1, 3, 10, 12, 14, and 16-18 are rejected under 35 U.S.C. 112(a) for failure to describe a sufficient number of different therapeutic molecules, diagnostic molecules, molecular complexes, or nanoparticles having a complement inhibitory protein attached thereto; peptides or aptamers that bind a complement inhibitory protein; and complement inhibitory proteins having unnatural amino acids and/or truncations that are capable of preventing or reducing CARPA. Although the claims do not recite compositions capable of preventing or reducing CARPA, these claims are interpreted in view of the specification and the title “Compositions and methods for prevention or reduction of CARPA”.
Claim 3 is also rejected under 35 U.S.C. 112(a) for failure to demonstrate that factor H bound to the aptamer of SEQ ID NO:5 is capable of preventing or reducing CARPA.
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 10, 12, and 16-17 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.
Claim 10 recites “the composition according to claim 3, wherein a) the linker comprises polyethylene glycol; and/or b) the linker is from 500 to 2500 D”. Polyethylene glycol is a polymer and reciting such polymer without its size makes the metes and bounds of the invention not clear. Reciting the linker size without its composition makes the metes and bounds of the invention not clear. The claim is interpreted as the composition according to claim 3, wherein the linker comprises polyethylene glycol polymer from 500 to 2500 D.
Claim 12 recites the complement inhibitory protein is a variant that includes unnatural amino acids and/or is truncated. The metes and bounds of the invention are not clear because a number and specific unnatural amino acids are not recited in the claim. Additionally, a number of truncated amino acids not recited in the claim.
Claims 16 and 17 recite “comprising at least or about 10 to about 30”. The metes and bounds of the invention are not clear because the specification fails to define numerical values corresponding to “about 10 to about 30”. The claims are interpreted as reciting “comprising from 10 to 30”.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Park et al. (IDS; ACS Nano. 2020 Sep 22;14(9):11950-11961).
Regarding claim 1, Park teaches a composition comprising silica nanoparticles coated with factor H (Abstract). Factor H is a complement inhibitory protein of instant invention. Upon coating factor H becomes attached to the nanoparticles.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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, 3, 12, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Meszaros et al. (IDS; Nanomedicine. 2016 May;12(4):1023-1031).
Regarding claim 1, Meszaros teaches a composition comprising a therapeutic molecule or nanoparticle with a complement inhibitory protein. Specifically, the reference teaches that several liposomal and micellar drugs and carriers, and therapeutic antibodies, were shown to activate complement and complement inhibitor factor H inhibited complement activation induced by the antifungal liposomal Amphotericin-B (AmBisome), Cremophor EL, and the anticancer monoclonal antibody rituximab (Abstract). The antifungal liposomal Amphotericin-B is a lipid nanoparticle and the anticancer monoclonal antibody rituximab is a therapeutic molecule of instant disclosure.
Additionally, Meszaros teaches that factor H is able to bind to the surface of liposomes and locally downregulate complement activation (pg. 1028, col. 1, par. 2) and a variant of factor H (mini-FH), owing to its small size, is rapidly cleared from the circulation (pg. 1028, col. 2, par. 2).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Meszaros by attaching factor H or its variant mini-FH to the surface of liposomes in order to locally downregulate complement activation (pg. 1028, col. 1, par. 2) and prevent rapid clearance of the factors from the circulation (pg. 1028, col. 2, par. 2). One having ordinary skill in the art would have been motivated to make such a change because factor H attached to the liposomes would only downregulate complement activation locally where the undesired activation by the liposomes occurs and the attachment of factor H variant mini-FH ensures its extended circulation. The use of such combination would have been desirable to those of ordinary skill in the art in order to prevent undesired downregulation of the complement all over the body.
One having ordinary skill in the art would have had a reasonable expectation of success because Meszaros has successfully combined these teachings.
Regarding claim 3, Meszaros teaches: (a) the nanoparticle is a lipid nanoparticle or liposome – specifically, the antifungal liposomal Amphotericin-B (Abstract) is Amphotericin-B drug encapsulated into liposomes; and (d) the complement inhibitory protein factor H (Abstract) is the protein selected from Table 1.
Regarding claim 12, Meszaros teaches the complement inhibitory protein is a variant that is truncated – “FH1-4 was less potent in inhibiting AmBisome- (Figure 4, A) and CrEL-induced (Figure 4, B)” (pg. 1026, col. 2, par. 2). FH1-4 is a truncated factor H as illustrated in Fig. 1B.
Regarding claim 18, Meszaros teaches the liposome comprises a therapeutic molecule encapsulated therein - the antifungal liposomal Amphotericin-B (Abstract) is Amphotericin-B drug encapsulated into liposomes.
Claims 3 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Park, as applied to claim 1 above, in view of Hermanson (Chapter 18, Editor(s): Greg T. Hermanson, Bioconjugate Techniques (Third Edition), Academic Press, 2013, Pages 787-838).
The teachings of Park have been set forth above.
Regarding claims 3 and 10, Park does not specifically teach nanoparticle is attached to the complement inhibitory protein by a flexible linker; and the linker comprises polyethylene glycol and the linker is from 500 to 2500 D.
Regarding claims 3 and 10, Hermanson teaches different ways of attaching biological molecules to each other and nanoparticles (the entire book).Regarding claim 3, Hermanson teaches benefits of using a linker comprising polyethylene glycol polymer, such as increase in the water solubility and a decrease in immunogenicity (pg. 787, col. 1, par. 1).
Regarding claim 10, Hermanson teaches using polyethylene glycol as a conjugation reagent for biological molecules (chapter 18, pg. 787, col. 1, par. 1). The number of repeat units in commercial PEG polymers can typically be anything from less than 50 to over 1100 (par. 2) and PEG-2000 has 53 units on average (col. 2, par. 1). The 2000 in PEG-2000 means average molecular mass is around 2000 D, meeting the limitation of claim 10 reciting the linker is from 500-2500 D.
Regarding attaching proteins to silica particles of Park, Hermanson teaches bis-NHS-PEG derivatives capable of conjugating to APTS-modified silica particles (Fig. 18.5 and pg. 792, col. 2, par. 1).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of Park, by employing a flexible PEG-2000-linker as taught by Hermanson, in order to attach factor H to the nanoparticles. One having ordinary skill in the art would have been motivated to make such a change because Hermanson teaches numerous benefits of polyethylene glycol as a linker “the rationale for using PEG polymers in bioconjugation applications includes a dramatic increase in the water solubility of modified molecules, a decrease in immunogenicity due to the shielding of modified molecules from the immune system, protection of modified protein and peptides from digestion by proteolytic enzymes, and effectively increasing their hydrodynamic volume and decreasing clearance rates by renal filtration …” (pg. 787, col. 1, par. 1). The use of such combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because polyethylene glycol linkers of Hermanson have been successfully used in a wide variety of attachments as evidenced by examples throughout chapter 18.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Meszaros, as applied to claim 1 above, in view of Lin et al. (Curr Probl Cancer. 2021 Oct;45(5):100796).
The teachings of Meszaros have been set forth above, specifically that therapeutic antibodies, were shown to activate complement and complement inhibitor factor H inhibited complement activation induced by the anticancer monoclonal antibody rituximab (Abstract).
Regarding claim 14, Meszaros does not specifically teach the therapeutic molecule comprises a radionuclide.
Regarding claim 14, Lin teaches applications of monoclonal antibody-based radiopharmaceuticals for imaging and therapy (Title). Lin also teaches the therapeutic molecule comprises a radionuclide. Specifically, Lin teaches that radiolabeled mAbs can be used in diagnostic imaging and the same mAb can then be radiolabeled with an analogous radionuclide for the delivery of beta-minus radiation or alpha-particles as part of a radioimmunotherapy.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the composition comprising a therapeutic antibody of Meszaros, by radiolabeling it for both diagnostic and therapeutic applications as taught by Lin, as an obvious matter of using of known technique of Meszaros to improve similar methods in the same way.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because both Meszaros and Lin are similarly drawn to monoclonal antibodies.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Park, as applied to claim 1 above.
Regarding claim 16, Park teaches a composition comprising silica nanoparticles coated with factor H (Abstract).
Park does not specifically teach 10 to 30 complement inhibitory protein molecules per nanoparticle. However, the reference teaches optimization of the coating protocol “BSA was used as a model protein and was incubated with SiNPs across a range of mass ratios from 1:16 to 2:1 BSA:SiNP … At 1:2 and higher BSA:SiNP ratios, the colloidal stability of BSA-coated SiNPs was greatly improved and nanoparticle sizes became consistent with the expected size of pristine SiNPs” (pg. 11952, col. 2, par. 3). Therefore, it is not the absolute number of protein molecules per nanoparticle that is important but the formation of a protein layer capable of providing sufficient colloidal stability to the nanoparticles; and the number of protein molecules per nanoparticle depends on particle size.
Since Applicant has not disclosed that the specific limitations recited in instant claims (number of complement inhibitory protein molecules per nanoparticle) are for any particular purpose or solve any stated problem and the prior art teaches that the number of complement inhibitory protein molecules per nanoparticle vary according to the nanoparticle size, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable protein load per nanoparticle disclosed by the prior art.
Subject Matter Free of the Prior Art
Claim 17 is free of the prior art. The prior art neither teaches nor suggests a therapeutic molecule, diagnostic molecule, molecular complex, or nanoparticle having a peptide or aptamer that binds a complement inhibitory protein attached thereto comprising 10 to 30 peptides or aptamers that bind a complement inhibitory protein per liposome or nanoparticle.
The closest prior art is Perret et al. (WO2015177740). The reference teaches SEQ ID NO:5 but fails to teach the composition comprising a therapeutic molecule, diagnostic molecule, molecular complex, or nanoparticle having an aptamer that binds a complement inhibitory protein attached thereto.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander Volkov whose telephone number is (571) 272-1899. The examiner can normally be reached M-F 9:00AM-5:00PM (EST).
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached on (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEXANDER ALEXANDROVIC VOLKOV/Examiner, Art Unit 1677
/REBECCA M GIERE/Primary Examiner, Art Unit 1677
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