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 .
Status of Application, Amendments and/or Claims
The amendment and Applicant’s arguments, filed 27 April 2026, have been entered in full. Claim 32 is withdrawn from consideration as being drawn to a non-elected invention. Claims 23, 33 and 34 are canceled. Claims 18, 19, 24, 36 and 37 are amended. Claims 18-22, 24-31, 35-37 are under examination.
Withdrawn Objections And/Or Rejections
The objection to the drawings as failing to comply with 37 CFR 1.84(p)(5), as set forth at page 3 of the previous Office Action (05 February 2026), is withdrawn in view of the amendment (27 April 2026).
The rejections to claims 18-31 and 35-37 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth at pages 4-6 of the previous Office Action (05 February 2026), are withdrawn in view of the amendment (27 April 2026).
The rejection to claims 18-22, 25-28, 31, 35 and 37 under 35 U.S.C. 102(a1) as being anticipated by Xu et al. (Biomaterials 33:1627-1639; 2012), as set forth at pages 6-7 of the previous Office Action (05 February 2026), is withdrawn in view of the amendment and Applicant’s arguments (27 April 2026).
The rejection to claims 18, 23, 24 and 30 under 35 U.S.C. 103 as being unpatentable over Xu et al. (Biomaterials 33:1627-1639; 2012) in view of Liu et al. (Biomaterials 31:9145-9155; 2010), as set forth at pages 8-12 of the previous Office Action (05 February 2026), is withdrawn in view of the amendment and Applicant’s arguments (27 April 2026).
The rejection to claim 29 under 35 U.S.C. 103 as being unpatentable over Xu et al. (Biomaterials 33:1627-1639; 2012) in view of Liu et al. (Biomaterials 31:9145-9155; 2010), as applied to claims 18, 23, 24, and further in view of Henning et al. (Nanoparticle multivalency counterbalances the ligand affinity loss upon PEGylation. Journal of Controlled Release 194:20-27; 2014), as set forth at pages 12-14 of the previous Office Action (05 February 2026), is withdrawn in view of the amendment and Applicant’s arguments (27 April 2026).
The rejection to claims 18 and 36 under 35 U.S.C. 103 as being unpatentable over Xu et al. (Biomaterials 33:1627-1639; 2012) in view of Zhang et al. (US 2010/0203142; published August 12, 2010), as set forth at pages 14-16 of the previous Office Action (05 February 2026), is withdrawn in view of the amendment and Applicant’s arguments (27 April 2026).
NEW CLAIM REJECTIONS/OBJECTIONS
Claim Rejections - 35 USC § 112(a) or 35 U.S.C. 112 (pre-AIA ), First paragraph, Written description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 18-22, 24-31, 35-37 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.
The claimed subject matter is not supported by an adequate written description.
The “first ligand” in the claimed nanoparticle is now required to have the function of initiating binding of the nanoparticle to a target cell but not initiating internalization of the nanoparticle cell into the target cell and further having the function of binding to the molecules recited in claim 36. The “second ligand” is now required to further have the function of binding to the molecules recited in claim 37.
The claims are drawn to a genus of molecules based entirely on function with no structural limitations. The instant claims encompass any/all ligands that have the required function.
MPEP§ 2163 states that the written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (show a structure is correlated with the function) OR through a sufficient description of a representative number of species (show a representative number of species that have the function. There must be enough species that are representative of the full breadth of the genus).
Regarding structure-function correlation:
A “first ligand” that initiates binding of a nanoparticle to a target cell but doesn’t initiate internalization of the nanoparticle into the target cell can include ligands having diverse structures such as polymers, aptamers, lipids, nucleic acids, chemical analogs, mRNA, etc.
“First and Second ligands/agents” that bind to angiotensin II receptor type 1 (AT1r), human neuropeptide Y1-receptor, C-X-C chemokine receptor type 4, heparan sulfate, a sialoglycoprotein, a ganglioside, or a mannose receptor, aVB3 integrin, aVB5 integrin, AT1r, legumain, a membrane-type matrix metalloproteinase or angiotensin converting enzyme (ACE) can include diverse structures such as growth factors, chemokines, cytokines, fusion proteins, polypeptides, polysaccharides, antibodies and fragments thereof.
The specification fails to teach the structural identifying characteristics of the claimed genus.
Even if the claimed genus was narrowed down solely to nucleic acids, polypeptides and antibodies that have the claimed function, the instant claims do not limit the number of modifications that can be made in the sequence of ligand/agent when compared to the wild-type sequence. The claims read on a sequence having any number of substitutions, deletions and/or insertions at every position with respect to a wild-type sequence as long as it retains the claimed function. There is not upper limit to the number of alterations that can be permitted in the claimed ligand/agent as long as they have the desired activity.
It is well recognized in the art that any modification (even a "conservative" substitution) to a critical structural region is likely to significantly alter its functional properties. It is known for nucleic acids as well as proteins, that even a single nucleotide or amino acid change or mutation can destroy the function of the biomolecule in many cases.
For example, Fenton et al. state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at non-conserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs (see entire reference)(Rheostat positions: A new classification of protein positions relevant to pharmacogenomics Medicinal Chemistry Research 29:1133-1146; 2020).
Bhattacharya et al. state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18)(Impact of genetic variation on three dimensional structure and function of proteins PLoS ONE 12(3): e0171355; 2017).
With respect to antibodies, the art recognizes that the formation of an intact antigen-binding site of all antibodies requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (see entire reference)(Al Qaraghuli et al. Antibody‑protein binding and conformational changes: identifying allosteric signaling pathways to engineer a better effector response. Nature Scientific Reports 10:13969, 2020).
Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines), and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well. Thus, a single protein can be bound by a very large and structurally diverse genus of antibodies (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes) (see entire reference)(The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS. Journal of Molecular Biology 334:103-118; 2003).
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function Rudikoff et al. (Single amino acid substitution altering antigen-binding specificity Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982).
The combination of evidentiary publications thus underscores a lack of structure-function correlation in polynucleotide, polypeptide and antibody molecules.
Regarding a representative number of species: The instant specification fails to describe a representative number of species to provide adequate written description of the claimed genus as per MPEP § 2163. A "representative number of species" means that the species, which is adequately described, is representative of the entire genus. When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case, the specification teaches EXP3174 and telmisartan as examples of “first ligands” that bind to angiotensin II Type 1 receptor (AT1r). The specification teaches that EXP3174 and telmisartan do not initiate internalization (paras 0013 and 0054). The specification teaches RGD-peptides, angiotensin-I and angiotensin-II as examples of “second ligands”. The specification teaches RGD-peptides bind to aVb3 and aVb5 integrins. The specification teaches angiotensin-I and angiotensin-II bind to AT1r (paras 0051 and 0056).
A disclosure of 2 species of “first ligands” is not representative of the claimed genus, which encompasses non-structurally defined moieties having the required function of initiating binding of the nanoparticle to a target cell but not initiating internalization of the nanoparticle cell into the target cell and further binding to angiotensin II receptor type 1 (AT1r), human neuropeptide Y1-receptor, C-X-C chemokine receptor type 4, heparan sulfate, a sialoglycoprotein, a ganglioside, or a mannose receptor.
A disclosure of 3 species of “second ligands” is not representative of the claimed genus, which encompasses non-structurally defined moieties, which now have the required function of binding to aVB3 integrin, aVB5 integrin, AT1r, legumain, a membrane-type matrix metalloproteinase or angiotensin converting enzyme (ACE).
There is substantial variation within the genus and the instant specification fails to describe a sufficient variety of species to reflect the variation within the genus. There must be enough species that are representative of the full breadth of the genus.
The claims depend on a recited property, where the claim covers every conceivable structure for achieving the stated property. The specification fails to teach the structural identifying characteristics that are applicable to the genus. The specification does not describe any correlation between the particular structure of the disclosed first ligands and second ligands and the structure of any ligand/agent that could be used in the claimed nanoparticle. There is no information regarding what structural features would likely be associated with such activity.
The skilled artisan cannot envision the detailed chemical structure of the encompassed claimed molecules (if any) which have the claimed activity without further testing, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification.
The courts have specifically stated that the skilled artisan cannot envision the detailed chemical structure of an encompassed polypeptide until the structure is disclosed, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. §112, first paragraph.
Claim Rejections - 35 USC § 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph
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.
Claim 24 is 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 24 is indefinite because it depends from canceled claim 23 (see MPEP 608.01(n)(V)). Therefore, the metes and bounds of claim 24 cannot be determined.
Conclusion
No claims are allowed.
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.
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/R.M.D/Examiner, Art Unit 1647 6/26/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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