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 .
Priority
The instant application claims priority to 371 National Stage Application PCT/CN2021/106043, filed July 13th, 2021, and foreign application CN202010692443.7, filed July 17th, 2020, under 35 U.S.C. 119(a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The priority date of July 17th, 2020, is acknowledged.
Nucleotide and/or Amino Acid Sequence Disclosures
Applicants’ arguments, see pg 10, filed July 9th, 2026, with respect to the objection to the sequence disclosures have been fully considered and are persuasive. The objection of the sequence disclosures has been withdrawn.
Claims Status
The claims listing filed on July 9th, 2026 is pending. Claims 23-28 are cancelled by applicant in response to Non-Final Office Action, filed April 9th, 2026. Claims 29-35 are being examined on the merits in this office action.
Claim Rejections - 35 USC § 112
Response to Arguments
Applicant’s arguments, see pg 10, filed July 9th, 2026, with respect to the rejection of claim 29 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 have been fully considered have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection for claims 30-34 is made due to new matter.
New Matter Rejection
Claims 30-34 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. While the applicant does have support for the fusion protein comprising (i) the cell penetrating peptide SEQ ID NO: 15, 17-18, 20, 27-28, 32-34, or 37 and (ii) the peptide of interests GFP, zinc-finger protein, anti-CRISPR protein, antibodies, reduced in practice, they do not have support for the possession of a fusion protein, wherein the fusion protein is not a naturally occurring protein.
Claim 30 recites the limitation “wherein the fusion protein is not a naturally occurring protein.” In applicants’ arguments, see pg 9 pgh 2 line 6, filed July 9th, 2026, applicant states that support for this amendment can be found throughout the specification. However, the specification does not support that the inventors possessed the complete recited genus of fusion proteins that are not a naturally occurring protein prior to the effective filing date. Furthermore, the applicant does not specifically point out where in the specification support for the limitation is found.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of he claimed genus [MPEP 2163 ii)].
The specification state that “it is easy to understand that the peptide of interest in the present application can be any desired protein or polypeptide” [pg 21 pgh 7]. The applicant does not specifically define an embodiment wherein the fusion protein is not naturally occurring.
The inventors provide direction by demonstrating cpp28 and its variants efficiency in delivering GFP into cells [Example 5 pg 48-50 and Fig 8-10]. Applicant constructed, expressed, and purified GFP-cpp28a, GFP-cpp28b, GFP-cpp28c, GFP-cpp28d, GFP-cpp28e, GFP-cpp28f, GFP-cpp28g, GFP-cpp28h, GFP-cpp28i, GFP-cpp28j, GFP-cpp28k, GFP-cpp28L, GFP-cpp28oS, GFP-cpp28aC, GFP-cpp28bC, GFP-cpp28cC, GFP-cpp28dC, GFP-cpp28dREC, GFP-cpp28oNT-1, GFP-cpp28oNT-2, GFP-cpp28oNT-3, GFP-cpp28aCQ1, GFP-cpp28aCQ2, GFP-cpp28aCQ3, GFP-cpp28aCNT, GFP-cpp28bCNT, GFP-cpp28cCNT and GFP-cpp28dCNT. The applicant also provides other embodiments of fusion proteins where the cell-penetrating peptide is SEQ ID NO: 10 (cpp28ori) and the peptide of interest is the anti-CRISPR protein, zinc finger protein, and the anti-HBeAg chimeric antibody 2A7, anti-HBcAg chimeric antibody 16D5, and anti-tyrosinase-related protein (TYRP1) chimeric antibody TA99 [Examples 6-8 pg 52-58 and Fig 17-21]. However, solely relying on GFP to represent the peptide of interest in the non-naturally occuring fusion proteins comprising the variants of SEQ ID NO:10-SEQ ID NO: 15, 17-18, 20, 27-28, 32-34, or 37- is introducing new matter because the other peptide of interests reduced to practice (e.g. anti-CRISPR protein and antibodies) are only comprised in a fusion protein with cell-penetrating peptide SEQ ID NO: 10. Furthermore, peptide of interests used in the fusion proteins reduced to practice by the applicant are not representative of the entire genus of peptide of interests in non-naturally occurring fusion proteins claimed. Nor, would one of ordinary skill in the art be able to attest to applicant’s intention to represent such a genus. While the applicant has support for the specific fusion protein embodiments reduced to practice, they do not have support for the complete genus of non-naturally occurring fusion proteins.
Claim 31 does not further limit the genus of the peptide of interest, as the non-naturally occurring fusion proteins reduced to practice do not represent the complete genus of comprising peptide of interests covalently linked to the cell-penetrating peptide directly or via a linker; the cell-penetrating peptides claimed linked to the N-terminal or C-terminal of a peptide of interest; the fusion protein further comprising an additional domain; or the fusion protein further comprising a tag domain. Thus, claim 31 introduces new matter and is rejected under the written description requirement.
Regarding claim 32, the specification states that it “is easy to understand that the molecule of interest in the present application can be any desired molecule [pg 23 pgh 5 line 1]. The applicant does not specifically define an embodiment wherein the conjugate is not naturally occurring. The inventors provide direction by demonstrating cpp28 and its variants efficiency in delivering GFP into cells [Example 5 pg 48-50 and Fig 8-10]. The applicant also provides other embodiments of conjugates where the cell-penetrating peptide is SEQ ID NO: 10 (cpp28ori) and the molecule of interest is the anti-CRISPR protein, zinc finger protein, and the anti-HBeAg chimeric antibody 2A7, anti-HBcAg chimeric antibody 16D5, and anti-tyrosinase-related protein (TYRP1) chimeric antibody TA99 [Examples 6-8 pg 52-58 and Fig 17-21]. However, solely relying on GFP to represent the peptide of interest in the non-naturally occurring conjugate comprising the cell-penetrating peptide of SEQ ID NO: 15, 17, 20, 27-28, 32-34, or 37, is introducing new matter because the other molecules of interests reduced to practice (e.g. anti-CRISPR protein and antibodies) are only comprised in a conjugate with cell-penetrating peptide SEQ ID NO: 10. The conjugates reduced to practice by the applicant are not representative of the entire genus of non-naturally occurring conjugates claimed. Nor, would one of ordinary skill in the art be able to attest to applicant’s intention to represent such a genus. While the applicant has support for the specific conjugate embodiments reduced to practice, they do not have support for the complete genus of non-naturally occurring conjugates.
Claim 33 does not further limit the genus of the molecule of interest, as the non-naturally occurring conjugates reduced to practice do not represent the complete genus of conjugates with a molecule of interest that is (1) a protein of interest or nucleic acid of interest; (2) covalently linked to the cell-penetrating peptide directly or via a linker; or (3) a cytotoxic agent or an active or traceable protein. Thus, claim 33 introduces new matter and is rejected under the written description requirement.
Regarding claim 34, the specification state that “it is easy to understand that the peptide of interest in the present application can be any desired protein or polypeptide” [pg 21 pgh 7]. The applicant does not specifically define an embodiment wherein the fusion protein is not naturally occurring. The inventors provide direction by demonstrating cpp28 and its variants efficiency in delivering GFP into cells [Example 5 pg 48-50 and Fig 8-10]. The applicant also provides other embodiments of fusion proteins where the cell-penetrating peptide is SEQ ID NO: 10 (cpp28ori) and the peptide of interest is the anti-CRISPR protein, zinc finger protein, and the anti-HBeAg chimeric antibody 2A7, anti-HBcAg chimeric antibody 16D5, and anti-tyrosinase-related protein (TYRP1) chimeric antibody TA99 [Examples 6-8 pg 52-58 and Fig 17-21]. However, solely relying on GFP to represent the peptide of interest in the non-naturally occurring fusion protein comprising the cell-penetrating peptide of SEQ ID NO: 15, 17, 20, 27-28, 32-34, or 37 is introducing new matter because the other peptide of interests reduced to practice (e.g. anti-CRISPR protein and antibodies) are only comprised in a fusion protein with cell-penetrating peptide SEQ ID NO: 10. The fusion proteins defined by the peptide of interests reduced to practice by the applicant are not representative of the entire genus of non-naturally occurring fusion proteins claimed. Nor, would one of ordinary skill in the art be able to attest to applicant’s intention to represent such a genus. While the applicant has support for the specific fusion protein embodiments reduced to practice, they do not have support for the complete genus of non-naturally occurring fusion proteins.
Claim Rejections - 35 USC § 101
Response to Arguments
Applicant’s arguments, see pg 11, filed July 9th, 2026, with respect to the rejection of claims 23-35 under 35 U.S.C. 101 because the claimed composition is a product of nature without any markedly different characteristics from any naturally occurring counterparts have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection for claims 30-35 is made in view of the amendments.
Claims 30-35 are rejected under 35 U.S.C. 101 because the claimed composition is a product of nature without any markedly different characteristics from any naturally occurring counterparts:
Laws of nature and natural phenomena, as identified by the courts, include
naturally occurring principles/relations and nature-based products that are
naturally occurring or that do not have markedly different characteristics
compared to what occurs in nature. The courts have often described these
exceptions using other terms, including "physical phenomena," "scientific
principles", "natural laws," and "products of nature." [MPEP 2106.04(c)]
Claim 30 recite a fusion protein that is not naturally occurring in nature. Such a protein is a product of nature because a recombinant fusion protein comprising a cell-penetrating peptide and a peptide of interest may still be indistinguishable for a protein sequence found in nature. See the analysis below.
Step 1: Does the claim fall into a statutory category of invention?
Yes, the claim is directed to a composition of matter, which falls into a category of invention.
Step 2A: Is the claim directed to a law of nature, a natural phenomenon
(product of nature) or an abstract idea?
Yes, the claims are directed to a product of nature because SEQ ID NO: 15 can be derived from a core protein of the Hepatitis B virus (HBV) [Accession Number: V5JE87 · V5JE87_HBV], aligning with residues 2-37. Similarly, SEQ ID NO: 20 can be derived from the external core antigen of the Horseshoe bat hepatitis B virus [Accession Number: U3M5R9· U3M5R9_9HEPA] and aligns with residues 178 to 217.
Regarding claims 30-31, the specification state that “it is easy to understand that the peptide of interest in the present application can be any desired protein or polypeptide” [pg 21 pgh 7]. Thus, the sequence of the peptide of interest is not limited from being the remaining sequence of the HBV proteins found in nature. A recombinant fusion protein, made by combining SEQ ID NO: 15 or 20 and the remaining HBV core protein or capsid sequence, while not naturally occurring, would be indistinguishable from HBV proteins and capsids that are products of nature. Thus, claims 30-31 read on a product of nature.
Regarding claims 32-33, the specification states that “it is easy to understand that the molecule of interest in the present application can be any desired molecule [pg 23 pgh 5 line 1]. Thus, the structure and sequence of the molecule of interest is not limited from reading on the remaining sequence of the HBV proteins found in nature. A recombinant conjugate, made by combining SEQ ID NO: 15 or 20 and the remaining HBV core protein or capsid sequence, while not naturally occurring, would be indistinguishable from HBV proteins and capsids that are products of nature. Thus, claims 32-33 read on a product of nature.
Regarding claim 34, the specification state that “it is easy to understand that the peptide of interest in the present application can be any desired protein or polypeptide” [pg 21 pgh 7]. Thus, the sequence of the peptide of interest is not limited from being the remaining sequence of the HBV proteins found in nature. Also, as evidenced by Ghaemi et al, the HBV capsid is a multimer because it has an icosahedral symmetry composed of 240 core capsid proteins (monomers) with identical sequences (Ghaemi, Z., Gruebele, M., & Tajkhorshid, E. (2021). Molecular mechanism of capsid disassembly in hepatitis B virus. Proceedings of the National Academy of Sciences of USA, 118(36), e2102530118.) [pg 1 pgh 2 line 1]. A multimer comprising recombinant fusion proteins made by combining SEQ ID NO: 20 and the remaining HBV capsid sequence, while not naturally occurring, would be indistinguishable from the HBV capsid that is a product of nature. Thus, claim 34 read on a product of nature.
Regarding claim 35, the specification state that “it is easy to understand that the peptide of interest in the present application can be any desired protein or polypeptide” [pg 21 pgh 7]. Thus, the sequence of the peptide of interest is not limited from being the remaining sequence of the HBV proteins found in nature. A complex comprising (1) (i) a recombinant fusion protein made by combining SEQ ID NO: 15 or 20 and the remaining HBV core protein or capsid sequence; and (2) a component like water non-covalently bound or complexed with (1), while not naturally occurring, would be indistinguishable from HBV core proteins and capsids that are products of nature. Thus, claim 35 read on a product of nature.
Step 2A Prong One: Does the claim recite an abstract idea, law of nature, or
natural phenomenon?
In the present case, the answer is yes because when a nature-based product is
derived from a naturally occurring thing, then the naturally occurring thing is the
counterpart. Section 2106.04 (b) recites:
When a law of nature or natural phenomenon is claimed as a physical product, the courts have often referred to the exception as a "product of nature". For example, the isolated DNA of Myriad and the primers of Ambry Genetics were described as products of nature by the courts. Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 580, 106 USPQ2d 1972, 1975 (2013); University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 758-59, 113 USPQ2d 1241, 1243 (Fed. Cir. 2014). As explained in those decisions, products of nature are considered to be an exception because they tie up the use of naturally occurring things, but they have been labeled as both laws of nature and natural phenomena. See Myriad Genetics, Inc., 569 U.S. at 590- 91, 106 USPQ2d at 1979 (claims to isolated DNA held ineligible because they claim “naturally occurring phenomena" and are "squarely within the law of nature exception")
Step 2A Prong Two: Does the claim recite additional elements that integrate
the judicial exception into a practical application?
Because the markedly different characteristics analysis is based on comparing the
characteristics of the claimed nature-based product and its counterpart, the second step
in the analysis is used to identify appropriate characteristics to compare. Appropriate
characteristics must be possessed by the claimed product, because it is the claim that
must define the invention to be patented. In the present case, while the cell-penetrating peptide does have a markedly different characteristic, the complete fusion proteins, conjugates, multimers, and complexes comprising the cell-penetrating peptide do not have a markedly different characteristic. As a whole, claims 30-35 are not defined by its ability to penetrate a cell. Rather, they only possess an element with a markedly different characteristic, which when integrated into protein sequences found in nature, are no longer indistinguishable from proteins that are naturally occurring.
Claim Rejections - 35 USC § 102
Response to Arguments
Applicant’s arguments, see pg 12, filed July 9th, 2026, with respect to the rejection of claims 23-29 under 35 U.S.C. 102 as being anticipated by Riedl et al. (Riedl, P., Reimann, J., & Schirmbeck, R. (2006). Complexes of DNA vaccines with cationic, antigenic peptides are potent, polyvalent CD8(+) T-cell-stimulating immunogens. Methods in molecular medicine, 127, 159–169.). have been fully considered and are persuasive. The rejection of claim 29 has been withdrawn.
Applicant’s arguments, see pg 13, filed July 9th, 2026, with respect to the rejection of claims 23-33 and 35 under 35 U.S.C. 102 as being anticipated by Chen et al (Chen HL, Su PY, Chang YS, Wu SY, Liao YD, et al. (2013) Identification of a Novel Antimicrobial Peptide from Human Hepatitis B Virus Core Protein Arginine-Rich Domain (ARD). PLOS Pathogens 9(6): e1003425.) have been fully considered and are persuasive. The rejection of claims 29-33 and 35 have been withdrawn.
Applicant’s arguments, see pg 13, filed July 9th, 2026, with respect to the rejection of claim 34 under 35 U.S.C. 102 as being anticipated by UniProt (Accession Number L0CNB4 · L0CNB4_HBV; entry 22-APR-2020). have been fully considered and are persuasive. The rejection of claim 34 has been withdrawn.
Claim Rejections - 35 USC § 103
Response to Arguments
Applicant’s arguments, see pg 13, filed July 9th, 2026, with respect to the rejection of claims 30-33 and 35 under 35 U.S.C. 103 as being unpatentable over Riedl et al. have been fully considered and are persuasive. The rejection of claims 30-33 and 35 has been withdrawn.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter.
The applicant’s cell-penetrating peptides consisting of SEQ ID NO: 15, 17-18, 20, 27-28, 32-34 and 37 no longer qualify as a product of nature because they pass prong two of the subject matter eligibility requirement tests. The claim recites the additional element “cell-penetrating” which amounts to significantly more than the judicial exception. SEQ ID NO:15 can be derived from a core protein of the Hepatitis B virus (HBV) [Accession Number: V5JE87 V5JE87_HBV], aligning with residues 2-37 and SEQ ID NO:20 can be derived from the external core antigen of the Horseshoe bat hepatitis B virus [Accession Number: U3M5R9. U3M5R9_9HEPA], aligning with residues 178 to 217. However, HBV core proteins and capsids do not inherently possess the cell-penetrating property. HBV enters a host cell through the low-affinity attachment of the virus to the cell surface, followed by high-affinity attachment to specific receptors, and subsequent endocytosis-mediated internalization [Abstract].
(Watashi, K., & Wakita, T. (2015). Hepatitis B Virus and Hepatitis D Virus Entry, Species Specificity, and Tissue Tropism. Cold Spring Harbor perspectives in medicine, 5(8), a021378.).
Thus, the invention possesses a markedly different characteristic than the HBV sequences found in nature.
Claim 29 is allowable over the closest prior art: Chen et al (Chen HL, Su PY, Chang YS, Wu SY, Liao YD, et al. (2013) Identification of a Novel Antimicrobial Peptide from Human Hepatitis B Virus Core Protein Arginine-Rich Domain (ARD). PLOS Pathogens 9(6): e1003425.) in view of Leonov et al. (US20200165613A1).
Chen et al. tested the antimicrobial activity of HBc peptides containing the arginine-rich domain at its C-terminus [Abstract]. Chen et al. found that the HBc147-183 peptide was not accumulated on the membrane and instead, enters the cytoplasm of S. aureus after penetrating the bacterial membrane [pg 11 pgh 4]. Chen et al. state that other arginine-rich peptides, such as Penetratin, Tat peptide, and oligoarginine, have been reported to be able to enter the mammalian cells as well [pg 11 pgh 5 line 1]. Chen does not teach a HBc peptide that comprises or consists of instant SEQ ID NO: 15, 17-18, 20, 27-28, 32-34, and 37.
Leonov et al. evidence that instant SEQ ID NO: 15 is comprised in the C-terminal ARD of HBV [0099]. Instant SEQ ID NO: 15 corresponds to residues 21-56 of Leonov’s SEQ ID NO: 53. However, both Leonov and Chen et al. do not teach that the specific sequences claimed by the applicant are what give their peptides the cell-penetrating property.
While Chen et al. motivate one of ordinary skill in the art to experiment with HBV peptides containing ARD regions, it would take hindsight reasoning to arrive at the claimed invention with Chen and Leonov’s teachings alone because they do not teach the specific sequences claimed. Moreover, it would take further experimentation to arrive at the claimed invention, ascertaining the invention’s novelty. Thus, cell-penetrating peptides consisting of SEQ ID NO: 15, 17-18, 20, 27-28, 32-34, and 37 are found to be allowable over the prior art.
Conclusion
Claim 29 is allowed. Claims 30-34 are rejected under 35 U.S.C. 112(a). Claims 30-35 are rejected under 35 U.S.C. 101.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SACHI JAUHARI whose telephone number is (571)272-3769. The examiner can normally be reached Mon-Fri 9-4.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SACHI JAUHARI/Examiner, Art Unit 1654 /LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654
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