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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-6 and 12, in the reply filed on 12/16/2025 is acknowledged. The traversal is on the ground(s) that unity of invention under 37 CFR 1.475(b)(3) is established. This is not found persuasive. Although unity of invention under 37 CFR 1.475(b)(3) does consist of a product, a process of use, and a method of making, the special technical feature that unites these inventions is not a special technical feature as it is anticipated by Xu and Yang (CN 110496229 A, published 11/26/2019). See prior Restriction Requirement.
The requirement is still deemed proper and is therefore made FINAL.
Applicant’s election of the species the cationic peptide of Formula I in the reply filed on 12/16/20254 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Status
Claims 1-12 and 14 are pending. Claims 7-11 and 14 are hereby withdrawn as non-elected inventions. Claims 1, 3-7, 9-12 and 14 were previously presented.
Priority
This application is the 371 national stage entry of PCT/CN2021/128313, filed 11/3/2021, which claims priority to CN202111151600.4, filed 9/29/2021, and CN202011455391.8, filed 12/10/2020. The priority date of 12/10/2020 is acknowledged although no translation has been made of record.
Information Disclosure Statement
The IDS’s filed 11/20/2022, 7/6/2023, 5/24/2024, and 3/19/2025 are under consideration. Any strikethrough is owed to lack of a date or an English translation.
Claim Interpretation
Claim 1 recites a polypeptide albumin nanoparticle is assembled from a cationic amphipathic polypeptide and serum albumin via non-covalent hydrophobic interaction and electrostatic attraction. The limitation “via non-covalent hydrophobic interaction and electrostatic attraction” describes the functional outcome of placing the structural elements from the claim – a cationic amphipathic polypeptide and serum albumin – together, according to the instant specification (Pg 3, line 29 – Pg 4, line 6; also see instant Figure 1). As such, the claim is being interpreted based upon the structural limitations – a nanoparticle comprising a cationic amphipathic polypeptide and serum albumin – where the described molecular interactions are a functional outcome or consequence of combining the structural elements.
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.
Claims 3, 5, 6, and 12 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.
Narrow and broad scope
Claim 3 recites that the hydrophilic part comprises any one or a combination of at least two of arginine, lysine, or histidine, preferably arginine (emphasis added). The scope of this claim is indefinite as it is unclear whether the claim is limited to only arginine or can comprise a combination of arginine, lysine, or histidine. For purposes of examination, the claim is being interpreted as the hydrophilic part comprises any one or a combination of at least two of arginine, lysine, or histidine.
Similarly language is recited in the following claims as well:
Claim 5 recites that, preferably, the lipid comprises any one or a combination of at least two of cholesterol and a derivative thereof or a fatty acid and a derivative thereof; preferably, the cationic amphipathic polypeptide has a structural formula represented by Formula I or II; preferably, the cationic amphipathic polypeptide has a primary structure of CH3CO-XRn-CONH2 or lipid-Rn-CONH2.
Claim 6 recites that the albumin comprises mammalian albumin; preferably the mammalian albumin comprises human serum albumin and/or bovine serum albumin.
Claim 12 recites a pharmaceutical composition comprising the polypeptide albumin nanoparticle of claim 1, preferably, the pharmaceutical composition further comprises any one or a combination of at least two of a pharmaceutically acceptable carrier, excipient, or diluent.
In each of these claims, it is unclear whether the narrower limitation, as indicated by the use of “preferably”, represents the scope of the claim or whether the broader limitation represents the scope of the claim. Thus, each of these claims is indefinite for this reason. For purposes of examination, the claims will be interpreted based upon the broadest limitation, which includes:
Claim 5 the lipid is any lipid and the cationic amphipathic polypeptide has a structural formula represented by Formula I or II or CH3CO-XRn-CONH2 or lipid-Rn-CONH2.
Claim 6 the albumin is a mammalian albumin.
Claim 12 the pharmaceutical composition comprises the polypeptide albumin nanoparticle of claim 1.
Multiple interpretations
Claim 3 is further rejected as indefinite because it is unclear whether “the hydrophilic part” refers to a portion of the cationic amphipathic polypeptide described in claim 1 or is another part of the polypeptide albumin nanoparticle. For purposes of examination, the claim is being interpreted as referring to the hydrophilic part of the cationic amphipathic polypeptide that is part of the nanoparticle.
Claim 4 is further rejected as indefinite because it is unclear whether “the hydrophobic part” refers to a portion of the cationic amphipathic polypeptide described in claim 1 or is another part of the polypeptide albumin nanoparticle. For purposes of examination, the claim is being interpreted as referring to the hydrophobic part of the cationic amphipathic polypeptide that is part of the nanoparticle.
Claim 5 is further rejected as indefinite because it is unclear whether the polypeptide albumin nanoparticle comprises 1) the hydrophobic amino acids or the lipid and the cationic amphipathic polypeptide comprises either Formula I or II or has a primary structure of CH3CO-XRn-CONH2 (“primary structure A”) or lipid-Rn-CONH2 (“primary structure B”) or 2) both the hydrophobic amino acids and the lipid and the cationic amphipathic polypeptide comprises either Formula I or II or has primary structure A or B. In essence, there are multiple ways to interpret the limitations of the claim, thus making it indefinite. For purposes of examination, the claim is being interpreted as the nanoparticle comprises either hydrophobic amino acids or lipids but not both in addition to the Formula I or II or primary structure A or B.
Antecedent basis
Claim 5 recites the limitation "the hydrophobic amino acid" in lines 1-2 and “the lipid” in line 4. There is insufficient antecedent basis for these limitations in the claim as there is no prior recitation of either a hydrophobic amino acid nor a lipid.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 recites that the cationic amphipathic polypeptide comprises a hydrophobic part and a hydrophilic part. As understood in the art and confirmed by the specification, amphipathic comprises both hydrophobic and hydrophilic parts (see instant specification Pg 1, lines 21-22). Thus, claim 2 does not further limit parent claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4, 6, and 12 are rejected under 35 U.S.C. 101 because they are directed to a judicial exception.
The Supreme Court has given a three-part test for patent eligibility (see flowchart of MPEP 2106(III)):
Are the claims drawn to a process, machine, manufacture, or composition of matter?
2a) If the claims pass the first test, are the claims drawn to a judicial exception (a law of nature, a natural phenomenon (product of nature), or an abstract idea)?
2b) If a judicial exception applies, do the claims recite additional elements that amount to significantly more than the judicial exception?
Applying the three-part test to the instant claims:
Regarding 1), the claims are drawn to a nanoparticle composed of a cationic amphipathic polypeptide and serum albumin, which is a composition of matter.
Regarding 2a), the nanoparticle claimed is a product of nature.
Claim 1 recites a polypeptide albumin nanoparticle is assembled from a cationic amphipathic polypeptide and serum albumin via non-covalent hydrophobic interaction and electrostatic attraction. Per the claim interpretation above, the instant specification makes clear the described molecular interactions between the cationic amphipathic polypeptide and serum albumin occur naturally due to their opposite charges and hydrophobic interactions. A cationic amphipathic polypeptide reads on the peptide LL-37, which occurs naturally in humans and can be found in plasma (Dürr et al. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta. 2006 Sep;1758(9):1408-25.; and Sørensen et al. The human antibacterial cathelicidin, hCAP-18, is bound to lipoproteins in plasma. J Biol Chem. 1999 Aug 6;274(32):22445-51.; see Abstracts). Because serum albumin is also found in human plasma, and the nanoparticles develop through a self-assembly mechanism, the claims read on this naturally-occurring product.
Regarding 2b), none of the claims above recite features that amount to significantly more than the natural product. Claims 2-4 merely recite elements that continue to read on LL-37, which has hydrophobic and hydrophilic parts/amino acids; claim 6 reads on human serum albumin found in human plasma; and claim 12 reads on blood as a pharmaceutical composition. As such, they do not contain elements added to the judicial exception sufficient to render the claims significantly more than the exception.
Taken together, the claims are drawn to patent ineligible subject matter and are rejected here.
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 (i.e., changing from AIA to pre-AIA ) 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(s) 1-4, 6, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cao et al. (Albumin Biomimetic Nanocorona Improves Tumor Targeting and Penetration of Synergistic Therapy of Metastatic Breast Cancer. Adv. Funct. Mater. 2017, 27, 1605679.; cited on IDS filed 3/19/2025).
Cao teaches albumin biomimetic nanocorona (DRI-s@HSA) that can highly accumulate and penetrate tumor tissues, such as breast cancer (Abstract). Cao teaches that the nanocorona comprises a nine D-arginine (r9) cell penetrating peptide, linked to 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) via disulfide bonds to form an amphiphilic peptide derivative (r9-S-S-DOPE), camouflaged with human serum albumin (Pg 2, left column, third paragraph – right column, first paragraph; Figure 1). Thus, claim 1 is anticipated.
Regarding claim 2, as stated above, the r9 peptide derivative has a hydrophilic (r9) and a hydrophobic (DOPE) part.
Regarding claim 3, as stated above, the r9 peptide derivative has a hydrophilic part that consists of arginine residues.
Regarding claim 4, as stated above, the r9 peptide derivative has a hydrophobic part that consists of DOPE.
Regarding claim 6, as stated above, the albumin is HSA.
Regarding claim 12, Cao describes the process by which the nanoparticles are generated in methanol and/or water and then dialyzed with water to remove methanol (Pg 11, left column, “Preparation and characterization of DRI” through “Preparation and characterization of DRI-S@HSA).
Claim(s) 1-4, 6, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yan et al. (Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury. Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6199-E6208.; cited on IDS filed 3/19/2025), as evidenced by Hou et al. (Melittin derived peptides for nanoparticle based siRNA transfection. Biomaterials. 2013 Apr;34(12):3110-9.).
Yan teaches a peptidic nanoparticle (NP) structures that features an amphipathic, cationic, cell-penetrating peptide (CPP) as a siRNA carrier that is stable in biological fluids and enables coordinated endosomal escape and release of siRNA into the cytoplasm (Pg E6199, right column, second paragraph). Yan describes the production of NPs, which consists of a self-assembling formulation where the cationic, amphipathic CPP p5RHH is mixed with siRNA in dilution buffer, incubated, and then stabilized for injection by mixing with albumin (Pg E6200, left column, “Formulation and characterization of peptide-siRNA NP”; Figure 1A). Thus, claim 1 is anticipated.
Regarding claim 2, the peptide p5RHH has the sequence VLTTGLPALISWIRRRHRRRHC, which exhibits both hydrophilic and hydrophobic parts (Pg E6200, left column, “Formulation and characterization of peptide-siRNA NP”).
Regarding claim 3, as stated above, p5RHH has a hydrophilic part that consists of arginine residues.
Regarding claim 4, as stated above, p5RHH has a hydrophobic part that consists of hydrophobic amino acids.
Regarding claim 6, the albumin is HSA, as evidenced by Hou et al. (see Pg 3111, “Preparation of peptide/siRNA nanoassemblies and analysis”; Melittin derived peptides for nanoparticle based siRNA transfection. Biomaterials. 2013 Apr;34(12):3110-9.).
Regarding claim 12, Yan describes the process by which the NP are generated in water, siRNA buffer, and HBSS (Pg E6206, right column, “p5RHH-siRNA NP Preparation”).
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Rejections in view of Ji et al.
Claim(s) 1-6 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Cao et al. (Albumin Biomimetic Nanocorona Improves Tumor Targeting and Penetration of Synergistic Therapy of Metastatic Breast Cancer. Adv. Funct. Mater. 2017, 27, 1605679.; cited on IDS filed 3/19/2025) in view of Ji et al. (Structure-tuned membrane active Ir-complexed oligoarginine overcomes cancer cell drug resistance and triggers immune responses in mice. Chem Sci. 2020 Aug 10;11(34):9126-9133.; cited on IDS filed 3/19/2025).
The teachings of Cao have been set forth above. Cao does not teach that the cationic amphipathic polypeptide has a structural formula represented by Formula I.
Ji teaches compounds as part of a series of membrane active iridium(III) complexed oligoarginine peptides with a new cell death mechanism capable of overcoming drug resistance as well as stimulating immunological responses (Abstract). Ji teaches the following compound
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250
204
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, where n is 3-8 (Figure 1). Complexing the oligoarginine peptides with 3-8 arginines with iridium(III) improved peptide retention time and cytotoxicity, as measured by IC50, with each additional arginine residue up to 8 further increasing the cytotoxicity (Figures 2 and 3).
Thus, regarding claim 5, Cao teaches albumin biomimetic nanocorona comprising the r9 CPP. Ji teaches iridium(III)-complexed oligoarginine peptides designed to treat cancer. Based on these teachings, it would be obvious to incorporate the Ir-oligoarginine peptide of Ji into the albumin biomimetic nanocorona of Cao. One skilled in the art would be motivated to do so in order to combine the therapeutic impacts of both Cao and Ji. One would have a reasonable expectation of success as Cao established that incorporation of the oligoarginine peptide r9 alone without iridium complexation could effectively treat cancer.
Additionally, per MPEP 2144.06(I), combining equivalents known for the same purpose is one legal precedent recognized by the courts as directed to common practices that normally require only ordinary skill in the art and are considered routine expedients: "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). By extension of this, it would be obvious to combine the albumin biomimetic nanocorona of Cao and the anticancer iridium (III) complexed oligoarginine peptide of Ji into one compound because both are designed to effectively inhibit/kill cancer or tumor cells.
Rejections in view of Hao et al.
Claim(s) 1-6 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Cao et al. (Albumin Biomimetic Nanocorona Improves Tumor Targeting and Penetration of Synergistic Therapy of Metastatic Breast Cancer. Adv. Funct. Mater. 2017, 27, 1605679.; cited on IDS filed 3/19/2025) in view of Hao et al. (CN107129519A, published 9/5/2017).
The teachings of Cao have been set forth above. Cao does not teach that the cationic amphipathic polypeptide has a structural formula represented by Formula I.
Hao teaches a metal iridium complex-based polypeptide fluorescent cyclization method and polypeptide thereof (Abstract). Hao teaches that studies have shown that limiting the conformation of a linear polypeptide increases the affinity and selectivity for binding to its receptor and its performance in the cyclized state is significantly better than its linear state. Additionally, some methods of cyclizing linear peptides have drawbacks (Pg 2, “background technology”, second paragraph). To overcome these drawbacks, Hao teaches cyclizing a linear peptide through a metal-iridium complex-based polypeptide, which has the advantages of being a simple process, quick and easy to implement, low toxicity, and high stability (Pg 3, “summary of invention”, first paragraph).
Hao teaches the structure
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332
548
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, wherein X1-Xn are amino acids and H is histidine (Figure 1). Hao teaches that the number of residues can be a positive integer greater than or equal to 0 (Pg 6, final paragraph – Pg 7, first paragraph).
Thus, regarding claim 5, Cao teaches albumin biomimetic nanocorona comprising the r9 CPP. Hao teaches a method to make cyclic peptides through metal iridium complexation; Hao further teaches that cyclized peptides show improvements over their linear counterparts, and the cyclization process through iridium complexation is easier and better for the aforementioned reasons compared to other cyclization methods. Based on these teachings, it would be obvious to incorporate the r9 peptide taught by Cao into the iridium complex taught by Hao. One skilled in the art would be motivated to do so in order to take advantages of the benefits of peptide cyclization taught by Hao. One would have a reasonable expectation of success as Cao indicated that r9 alone as a linear peptide without iridium complexation could be effectively used in nanocoronas to treat cancer and Hao established that the cyclization of linear peptides improved their activity.
Prior Art Cited but not Referenced
CN 110548142A (published 12/10/2019) teaches nanoparticles comprising BSA, the photosensitizer chlorin e6, and the cationic amphipathic peptide melittin
Conclusion
No claim is allowed.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/FRED H REYNOLDS/Primary Examiner, Art Unit 1658