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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/15/2025 has been entered.
Priority
This application is a 371 of PCT/US2020/016256 filed 01/31/2020 which claims benefit of provisional application 62/800,093 filed 02/01/2019. 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.
Status of the Claims
Applicant’s amendment filed on 03/28/2025 is acknowledged.
Claims 1-3, 6, 8, 10, 11, 14, 16-22, 25, 27, 29, 30 and 32 are pending. Claims 1, 10, 11 and 16 were amended. Claims 27, 29, 30 and 32 were withdrawn.
Claims 1-3, 6, 8, 10, 11, 14, 16-22 and 25 (claim set as filed on 03/28/2025) are examined on the merits herein.
Withdrawal of Rejections
The response and amendment filed on 03/28/2025 are acknowledged. All of the amendment and arguments have been thoroughly reviewed and considered.
For the purposes of clarity of the record, the reasons for the Examiner's withdrawal and/o maintaining if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner's response to arguments section.
The previous claims 10, 11, 14 and 16 rejection under 35 U.S.C. 112(b) has been withdrawn necessitated amendment of claims 10.
The previous claims 1, 10, 17, 18 and 25 rejection under 35 U.S.C. 102(a)(1) has been withdrawn necessitated amendment of claims 1.
The previous claims 1, 10 and 16 rejection under 35 U.S.C. 103 over Chang in view of Nie has been withdrawn necessitated amendment of claims 1.
New Rejections
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.
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.
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Claims 1-3, 6, 8, 10, 11, 14, 17-22 and 25 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.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitations are: “configured to” in claim 1, lines 4 and 5 and in claim 10, line 3. Although “configured to” is present in claim 16, line 2, claim 16 is not interpreted under 35 U.S.C. 112(f) since it recites the structure, i.e. Coomassie blue.
Because these claim limitations are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, they are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. The instant specification does not describe a required structure necessary for the affinity domain to non-covalently bind a macromolecule; for a hydrophobic domain to interact with a plasma membrane; and for a small molecule to non-covalently bind the peptide, polypeptide or protein. Although the specification provides examples of the corresponding structures, these structures are described to be used for some embodiments and not as required structures. The structural requirements are described broadly. For instance, regarding affinity domain the specification states: “Typically, the affinity domain is not specific for noncovalently binding to any particular nucleic acid sequence, but rather can generally bind to nucleic acids, or at least general types of nucleic acids ( e.g., double-stranded DNA, double-stranded RNA, and the like) regardless of specific sequence.” (p. 11, lines 6-9) and “Many binding agents that bind to peptides, polypeptides, and proteins are known and are encompassed by the present disclosure” (p. 14, lines 29-30) and regarding hydrophobic domain: “The hydrophobic domain is any domain that can interact with a plasma membrane of a cell.” (p. 15, lines 3-4). Therefore, the claims 1 and 10 are indefinite and are rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Claims 2, 3, 6, 8, 11, 14, 17-22 and 25 do not resolve the issues mentioned above and are rejected.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3 and 17-22 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by Sheng (Sheng et al. Colloids and Surfaces B:Biosurfaces, 2014, 116, 32-40) as evidenced by Ohvo-Rekila (Ohvo-Rekila et al. Progress in Lipid Research, 2002, 41, 66-97).
Regarding claim 1, Sheng teaches cholesterol-based cationic lipids for gene delivery (Title). Sheng describes that compound includes natural cholesterol as hydrophobic block, corresponding to instant hydrophobic domain, and natural cationic amino acids L-lysine or L-histidine, corresponding to instant affinity domain, conjugated by a flexible linker (p. 35, left column). Cholesterol and amino acids are small molecules. Cholesterol is known to interact with plasma membrane (Abstract) as evidenced by Ohvo-Rekila. Positively charged L-lysine and L-histidine can non-covalently bind negatively charged DNA and L-lysine bearing lipid showed higher DNA binding affinity as disclosed by Sheng (Abstract). Sheng mentions that the cholesterol-cationic lipid bearing L-lysine showed the cellular uptake capacities for plasmid DNA 2.58–1.98 folds higher than that of lipofectamine2000 (p. 38, right column, Figure 6). The cationic lipid of Sheng corresponds to instant bifunctional tag and hence Sheng teaching as evidenced by Ohvo-Rekila anticipates claim 1.
Regarding claims 2 and 3, Sheng teaches plasmid DNA as the macromolecule which is a double stranded DNA (p. 34, right column, 3rd paragraph). Thus, Sheng teaching as evidenced by Ohvo-Rekila anticipates claims 2 and 3.
Regarding claims 17-20, Sheng teaches cholesterol as hydrophobic domain (Abstract). Cholesterol is a cyclic hydrocarbon with 27 carbons and is a steroid that reads on claims 17-20 limitations. Thus, Sheng teaching as evidenced by Ohvo-Rekila anticipates claims 17-20 obvious.
Regarding claims 21 and 22, Sheng teaches that the hydrophobic and the affinity domains are connected through linker which is: “flexible 1,6-hexanediol linkers with biodegradable carbonate ester or undegradable ether as the linkage bonds (p. 35, left column, Figure 1). The 1.6-hexanediol linker is a linear linker conjugating single hydrophobic domain (cholesterol) with single affinity domain (cationic amino acid). Thus, Sheng teaching as evidenced by Ohvo-Rekila anticipates claims 21 and 22 obvious.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Sheng (Sheng et al. Colloids and Surfaces B:Biosurfaces, 2014, 116, 32-40) as evidenced by Ohvo-Rekila (Ohvo-Rekila et al. Progress in Lipid Research, 2002, 41, 66-97) as applied to claims 1 and 2 above, and further in view of Gaugain (Gaugain et al. Biochemistry, 1978, 17, 5078-5088 on record in IDS).
The teaching of Sheng has been set forth above.
Sheng does not teach the affinity domain to comprise an intercalating agent.
Gaugain teaches intercalators, ethidium homodimer and acridine ethidium heterodimer that have high affinity for DNA and have fluorescent properties (Abstract). Gaugain discloses large increase in fluorescence of these intercalators when binding DNA making them useful as fluorescent probes (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use intercalators from Gaugain teaching as small molecule DNA-binding domain in compounds for delivery of nucleic acids described in Sheng teaching. One would have been motivated to make this modification because Gaugain teaches high affinity of intercalating compounds for DNA and fluorescent properties of the intercalators will make it possible to monitor the delivery process. A skilled artisan would have reasonably expected success in this modification since Sheng and Gaugain teach compounds interacting with nucleic acids. Thus, Sheng and Gaugain teachings as evidenced by Ohvo-Rekila render claim 8 obvious.
Claims 1-3, 6, 10, 11, 14, 17-22 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 7404969 B2 on record in IDS) as evidenced by Ohvo-Rekila (Ohvo-Rekila et al. Progress in Lipid Research, 2002, 41, 66-97).
Regarding claim 1, Chen teaches compounds, compositions and methods to facilitate delivery of various molecules into cells (column 6, lines 29-31). The molecules include macromolecules such as nucleic acids, proteins and antibodies (column 6, lines 38-42). Chen discloses cationic lipids as compounds that can interact with macromolecules (column 4, lines 57-59) due to electrostatic interaction (column 5, line 1). Chen describes multiple cationic and neutral lipids which are small molecules as delivery agents (columns 8-28). Many cationic lipid, e.g. neutral CLI (column 8, lines 11-31) or positively charged CLIII (column 9, lines 1-14) include cholesterol conjugated to a small molecule by a linker. Cholesterol is known to interact with plasma membrane (Abstract) and is a hydrophobic compound (p. 72, 2nd paragraph) as evidenced by Ohvo-Rekila. Thus, cationic lipid CLI or CLIII can be envisioned as a small molecule that can non-covalently bind a macromolecule by electrostatic interaction and that is conjugated with cholesterol which is a hydrophobic small molecule that can interact with the plasma membrane. Therefore, the cationic lipids of Chen teaching serve function of instant bifunctional tag.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use cationic lipids including cholesterol as one of the groups from Chen teaching as bifunctional tags. One would have been motivated to do that because Chen teaches that cationic lipids can interact with macromolecules due to electrostatic interaction and cholesterol can interact with the plasma membrane as evidenced by Ohvo-Rekila. A skilled artisan would have reasonably expected success in this application since Chen teaches compounds and methods for delivery of various molecules to cells. Therefore, Chen teaching as evidenced by Ohvo-Rekila renders claim 1 obvious.
Regarding claims 2, 3 and 6, Chen teaches compounds and methods for delivery of nucleic acids and siRNA (column 6, lines 38, 45). Chen mentions that siRNA is double-stranded (column 51, lines 55- 56). Thus, Chen teaching as evidenced by Ohvo-Rekila renders claims 2, 3 and 6 obvious.
Regarding claims 10, 11 and 14, Chen teaches that the invented novel cationic lipids can effectively deliver different biologically active molecules, such as peptides, proteins and antibodies which includes monoclonal, chimeric and humanized antibodies (column 1, lines 25-29). Thus, Chen teaching as evidenced by Ohvo-Rekila renders claims 10, 11 and 14 obvious.
Regarding claims 17-20, Chen teaches cholesterol in the cationic lipid compound (column 8, lines 11-31) that can be envisioned as hydrophobic domain as described above. Cholesterol is a cyclic hydrocarbon with 27 carbons and is a steroid that reads on claims 17-20 limitations. Thus, Chen teaching as evidenced by Ohvo-Rekila renders claims 17-20 obvious.
Regarding claims 21 and 22, Chen teaches compounds having cholesterol attached via a linker, e.g. as shown for compound CLI. A linker is described as: “ a C1 to C10 alkyl, alkyl ether, polyether, or polyethylene glycol linker” (column 8, lines 32-33) and is a linear linker conjugating hydrophobic domain (cholesterol) with affinity domain (cationic lipid). Thus, Chen teaching as evidenced by Ohvo-Rekila renders claims 21 and 22 obvious.
Regarding claim 25, Chen teaches composition comprising the biologically active molecule such as siRNA or miRNA interacting with cationic lipid non-covalently (column 31, lines 55-60) and described preparation of the composition by mixing the components (column 129, lines 27-29). Chen discloses that the composition contains the physiologically-acceptable carrier: “The formulated siNA compositions of the present invention can be administered either alone or in mixture with a physiologically-acceptable carrier (such as physiological saline or phosphate buffer) selected in accordance with the route of administration and standard pharmaceutical practice” (column 134, lines 51-55). Thus, Chen teaching as evidenced by Ohvo-Rekila renders claim 25 obvious.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 7404969 B2 on record in IDS) as evidenced by Ohvo-Rekila (Ohvo-Rekila et al. Progress in Lipid Research, 2002, 41, 66-97) as applied to claims 1 and 10 above, and further in view of Nie (Nie et al. Cancer Therapy, 2012, 8, 884-891 on record in IDS).
The teaching of Chen has been set forth above.
Chen does not teach Coomassie blue as a protein binding agent.
Nie teaches nanoparticles with covalently linked Coomassie Blue for brain tumor visualization (Abstract). Nie mentions advantages of Coomassie blue for visualization: “It has a vivid blue color in the pH 3 to 11 range, with a very high molar extinction coefficient. It is also known to be safe for intravenous injection into the human body, even at very high doses” (p. 885, left column, 2nd paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Chen bifunctional tag by including Coomassie blue for protein binding from Nie teaching instead of compound binding proteins in cationic lipids in Chen teaching. One would have been motivated to make this modification because Nie teaches efficient tumor staining with Coomassie blue and staining of peptides/proteins with Coomassie blue would allow to visualize macromolecule delivery to target cell. A skilled artisan would have reasonably expected success in this modification since Chen and Nie teach carriers for intracellular delivery, Chen provides bifunctional tag for macrobiomolecule delivery and Nie provides visualization method for efficiency of delivery. Thus, Chen and Nie teachings as evidenced by Ohvo-Rekila render claim 16 obvious.
Response to Arguments
Applicant's arguments filed 03/28/2025 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to prior art of Chang are moot because the 35 U.S.C. 102(a)(1)rejection and 35 U.S.C. 103 rejection based on prior art of Chang have been withdrawn necessitated amendment of claims 1.
In response to Applicant’s arguments (addressing pages 14-16 of the Remarks) that: “Chen teaches a list of cationic lipids and neutral lipids, which are combined with a polyethyleneglycol-diacylglycerol (PEG-DAG, PEG-cholesterol, or PEG-DMB) in various permutations and combinations to form the FMC or LNP compositions for encapsulation of nucleic acid for intracellular delivery. Chen does not teach a bifunctional tag molecule consisting of an affinity domain and a hydrophobic domain, wherein the affinity domain and the hydrophobic domain are covalently conjugated, wherein each of these domains is a small molecule, as required by the subject matter encompassed by the present claims.”, these arguments are not persuasive because:
Chen teaches not only formulated molecular compositions (FMC) and lipid nanoparticles
(LNP), but also lipid compounds for delivery of molecules: “The present invention features compounds, compositions, and methods to facilitate delivery of various molecules into a biological system, such as cell” (column 6, lines 29-31). Instant claims are directed to a bifunctional tag, compound composed of two small molecules that can bind macromolecule and interact with a membrane. That does not exclude further incorporation of the tagged molecule in the composition or in the nanoparticle. Whether compounds are used as separate entities or within a composition with other components is not within the scope of the claims since claims are not directed to delivery of macromolecule or to compositions and formulations used for delivery; and
Chen teaches various compounds which are cationic lipids. Compounds of Chen
invention can interact with various molecules since Chen teaches delivery of different molecules, not only nucleic acids: “ … the delivery of molecules, including but not limited to small molecules, lipids, nucleosides, nucleotides, nucleic acids, polynucleotides, oligonucleotides, antibodies, toxins, negatively charged polymers and other polymers, for example proteins, peptides, hormones, carbohydrates, or polyamines, across cellular membranes.” (column 6, lines 37-42). Chen describes multiple compounds which can be neutral or charged, e.g. neutral compound CLI (column 8) or positively charged compound CLIII (column 9). Different structure of compounds provides binding to different targets. For instance, the positively charged compound can bind negatively charged nucleic acids. These compounds can be envisioned as composed of a small molecule, that can bind to the target macromolecules via electrostatic or hydrophobic interaction and which corresponds to affinity domain, conjugated by a linker to a hydrophobic small molecule, cholesterol (R4 in CLI or CLIII), that can interact with a membrane as evidenced by Ohvo-Rekila (Abstract). Thus, the cationic lipid of Chen teaching has structure and performs function of instant bifunctional tag. Therefore, the 35 U.S.C. 103 rejection is maintained and modified necessitated by amendment of the claims.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIOUBOV G KOROTCHKINA whose telephone number is (571)270-0911. The examiner can normally be reached Monday-Friday: 8:00-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila G Landau can be reached at (571)272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.G.K./ Examiner, Art Unit 1653 /SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653