DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. The response dated 9/4/2025 is acknowledged and entered into record. Claims 42-44 are currently pending.
3. Applicant’s election without traverse of species a) Intramolecular dipole-dipole interaction represented by claims 42 and 43, in the reply filed 4 September 2025 is acknowledged.
4. Claim 44 is withdrawn from further consideration pursuant to 37 CFR1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4 September 2025.
5. The requirement is deemed proper and is therefore made FINAL.
6. Claims 42 and 43 are under consideration in the instant application.
Claim Rejections - 35 USC § 112-Second paragraph
7. 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.
8. 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.
9. Claims 42 and 43 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 pre-AIA the applicant regards as the invention.
10. Claim 42 is rejected under 35 U.S.C. 112, second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. While all of the technical details of a method need not be recited, the claims should include enough information to clearly and accurately describe the invention and how it is to be practiced. The omitted steps are for example: an active method step directed to “determining the extent….”. Please note that for prior art application, the broadest reasonable interpretation of claim 42 will be considered to be comprising - combining a polypeptide with citrate – which essentially is the only active method step in the claim. Appropriate correction is required.
11. Claim 43 is rejected as it depends from cancelled claim 41. Therefore, it is unclear as to what is encompassed by the claim as it depends from canceled subject matter. The claim fails to identify the metes and bounds of the related subject matter and how that could be ascertained in the stated invention. Appropriate correction is required. For instant examination, claim 43 will be construed as depending from claim 42.
Claim Rejections - 35 USC § 101
12. 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.
13. Claims 42-43 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) a method comprising determining the association of insolubility of a polypeptide with the naturally occurring intramolecular interactions (e.g. chemical bonds within the molecule) of the polypeptide, which is a law of nature/natural principle. The teaching that intramolecular interactions of a protein (polypeptide) are natural is evident from the teachings of Roberson AD (TRENDS in Biochem Sci 27: 521-526, 2002 – full article: for example, Abstract; Fig. 2). The combination of steps recited in the claims taken in totality, including a conditional step comprising combining the polypeptide with citrate, only if there is a significant said association, is not sufficient to qualify as a patent-eligible practical application as the claim covers every substantial practical application of the judicial exception (emphasis added). The determining of the association of relative aqueous insolubility of a polypeptide with the naturally present intramolecular interactions of the polypeptide do not impose meaningful limits on the claim scope, so that others are not substantially foreclosed from using the judicial exception(s). The claims recite steps in addition to the judicial exception(s) at a high level of generality such that substantially all practical applications of the judicial exception(s) are covered: for example, combining a polypeptide with citrate, which was known in the prior art. Rossomando et al (WO 2007/103182, 9/13/2007) teach a pharmaceutical composition comprising a protein (Neublastin) and citrate (page 22, lines 9-11).
14. The “determining” step (i.e., determining of the association of insolubility of a polypeptide with the naturally occurring intramolecular interactions of the polypeptide wherein the insolubility is at a pH below the natural isoelectric point of the polypeptide) do not impose meaningful limits on the claim scope, so that others are not substantially foreclosed from using the judicial exception(s), as this limitation is directed to an abstract idea or judgement that can be derived, for example, using mathematical formulas or equations, which demonstrate a law of nature. For example, Franco et al (Fluid Phase Equil 306: 242-250, 2011) teach the relation between protein solubility and solution pH, by a mathematical development for analytical expression of solubility curve as a function of ionization, pH and solubility at the isoelectric point (Abstract). The reference teaches a method for calculating protein solubility depending on pH in the vicinity of the isoelectric point by applying a mathematical equation to all ionizable groups of the protein (i.e. considering the intramolecular dipole-dipole interactions) (page 243, col 1, para 2; pages 243-246). The evaluation of results based upon observation and judgement is equivalent to mental processes or concepts performed in the human mind. The recited limitations are no more than a field of use or merely involve insignificant extra-solution activity to the judicial exception; e.g., data gathering, as the isoelectric point and intramolecular dipole-dipole interactions are natural or inherent to the polypeptide. Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 79, 101 USPQ2d 1961, 1968 (2012) (Mayo). Furthermore, combining the protein with citrate or different carriers to enhance solubility, in addition to the judicial exception, is well-understood, conventional or routine in the relevant field (for reasons stated above) and must be taken by others to apply the judicial exception. (See Guidance For Determining Subject Matter Eligibility Of Claims Reciting Or Involving Laws of Nature, Natural Phenomena, & Natural Products (Guidance) dated October 2019).
15. Dependent claim(s) 43 when analyzed as a whole is held to be patent ineligible under 35 U.S.C. 101 because the additional recited limitation(s) fail(s) to establish that the claim(s) is/are not directed to an abstract idea for reasons stated above. Looking to the claim as a whole, none of the steps considered individually or in combination include additional elements that are sufficient to amount to significantly more than the judicial exception and ineligible step/s, because the claimed steps are routine, conventional and must necessarily be performed to accomplish the method of claim 43. Thus, the claims are directed to patent ineligible matter. Bilski v. Kappos, 75 Fed. Reg. 43922, July 27, 2010 (2010 Interim Bilski Guidance).
Claim Rejections - 35 USC § 102
16. 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.
NOTE for following rejections: For reasons stated in paragraph 10 of this Office Action, claim 42 will be given its broadest reasonable interpretation as a method comprising combining a polypeptide with citrate, given this is the only active method step.
17. Claim 42 is rejected under AIA 35 U.S.C. 102(a)(1) as being anticipated by Rossomando et al (WO 2007/103182, 9/13/2007).
18. Claim 42 is directed to a method comprising determining the extent to which the relative aqueous insolubility of a polypeptide at particular pH is associated with dipole-dipole interactions of the polypeptide, wherein the pH is below the isoelectric point of the polypeptide; and if the relative insolubility is significantly associated with dipole-dipole interactions, combining the polypeptide with citrate to enhance solubility (claim 42).
19. Rossomando et al teach a pharmaceutical composition comprising Neublastin polypeptide (protein) combined with sodium citrate for administration in subjects (page 2, lines 23-24; page 22, lines 9-11; page 13, lines 21-22), wherein the composition contains carriers which are viscosity improving (enhancing solubility) agents for administration (page 14, line 18). Since sodium citrate is combined with the protein or polypeptide, and since sodium citrate is a carrier used for intravenous administration, it would inherently be expected to enhance the solubility of the protein. Please note that the claim limitation “to enhance the solubility of the polypeptide”, does not indicate an active step, only implies an intended outcome. The limitation reciting “combining the polypeptide with citrate” is the only active step to be performed, and “to enhance the solubility…” will necessarily follow the active step, therefore, does not add patentability to the claimed method. Because Rossomando et al teach the method step of claim 42, the reference anticipates the invention.
20. Claims 42 and 43 are rejected under AIA 35 U.S.C. 102(a)(1) as being anticipated by Arakawa et al (Meth Enzymol 114: 49-77, 1985).
21. Claim 43 recites that the dipole-dipole interactions are intramolecular.
22. Arakawa et al teach that proteins are complex molecules having positive and negative charges, where Z is the net charge of the protein (page 54, para 2). The reference teaches the solubility of a protein (carboxyhemoglobin) in various electrolytes including sodium citrate (Na3 citrate), wherein at the isoelectric point (Z=0) the protein solubility is at a minimum, and is increased (enhanced) by addition of salt (page 55, para 1; FIG. 3, FIG. 5). The reference therefore, anticipates the instant method step of claim 42 reciting combining the protein (or polypeptide) with citrate to enhance the solubility of the protein. As the solubility is based upon the net charge of the protein, the claimed dipole-dipole interactions are expected to be intramolecular, absent any evidence to the contrary. Arakawa et al therefore, anticipate the instantly recited method.
23. Claim 42 is rejected under AIA 35 U.S.C. 102(a)(1) as being anticipated by Weingartner et al (J Food Sci 48: 256-257, 1983 -abstract only).
24. Weingartner et al teach that addition of calcium citrate to soybean beverage (soy protein or polypeptide) caused a decrease in beverage viscosity (enhance solubility). Since Weingartner et al teach the active method step of claim 42, the reference anticipates the claimed method.
Conclusion
25. No claims are allowed.
26. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aditi Dutt whose telephone number is (571)272-9037. The examiner can normally be reached on M-F 9:00am-5:00pm.
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/A. D./
Examiner, Art Unit 1675
6 February 2026
/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675