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 .
Restriction/Election
Applicant's election with traverse of group I, claims 1-5, 7, 8, and 11-14, in the reply filed on 10/06/22 is acknowledged. The traversal is on the ground(s) that the applied art does not break unity of invention because it does not render obvious the instant claims. This is not found persuasive.
Applicants have submitted that one of ordinary skill in the art would have no reasoning or motivation to choose a PEG of MW 20,000 to 40,000. Applicants supported this argument by referring to example 6, in which it was observed that the PEG of higher molecular wight had less skin irritation at the injection site. However, this example does not provide any hard data that can be used to determine the significance, as stated. Without a metric by which an unexpected result can be determined, the statement regarding skin irritation is not persuasive to show an unexpected result.
Similarly, examples 7-8 do not have any objective data, as the examples only show tables of what was prepared, and the specification does not provide objective standards for what is considered a statistically significant measure of the results of any of these examples. For example, the results of example 8 states the following for mPEG20000CY group:
“Each animal was not observed to die or in dying; the body weights and the food intakes were reduced temporarily; the coagulation function and the blood biochemical index were not seen to be obviously abnormal; and through the gross dissection, each organ was not observed to obviously abnormal.”
This is description of the results does not show an objectively measured result that is unexpected or significant. As such, applicants arguments are not persuasive to show that there is no motivation to combine the two references or to show an unexpected result.
In response to applicant's argument that the examples of the specification show advantages to using high MW PEG vs. lower MW PEG, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). The below rejection lays out the teaching of Hai and DeNardo, and DeNardo provides clear motivation to use high MW PEG instead of lower MW PEG. Absent any objective evidence of an unexpected result, the combined teachings provide motivation to use the PEG20000-40000, even though they may not be the same motivation as applicants have presented.
Furthermore, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., no skin irritation, reduced hemolytic effects) are not recited in the rejected claim(s), as the elected invention is drawn to the product, and not to a method of treatment. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The requirement is still deemed proper and is therefore made FINAL.
Claims 6, 9-10 and 15-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 02/26/26.
Claim Rejections 35 USC 112(B)
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.
Regarding claim 12, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 12, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections 35 USC 112(A)
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 1-5, 7, 8 and 11-14 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 claims contain 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.
MPEP § 2163 states that "the written description requirement for a genus must 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 applicant was in possession of the claimed genus (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
For written description, the analysis (a) considers actual reduction to practice, (b) disclosure of drawing or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties, functional characteristics when coupled with known or disclosed and (d) representative number of examples.
(a) actual reduction to practice/(b) disclosure of drawing or structural chemical formulas:
The specification only discloses SEQ ID NO: 1 as the peptide of the invention, with no examples of sequences that are less than 100% identical to the PIBC sequence. The claims are drawn to peptides as low as 60% identical to the 37 residue PIBC peptide, which allows for up to 14 amino acid substitutions. Not only are there no examples of sequences disclosed other than SEQ ID NO: 1, there are also no examples reduced to practice, other than SEQ ID NO: 1 with PEG20000 or PEG40000 at the -N or -C terminus.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties
The specification does not provide any guidance as to which amino acids can be substituted and which portions of the peptide are required to retain the PIBC function. Li teaches that the PIBC peptide (commonly known in the art as p37) was specifically designed to inhibit gp96, and that intramolecular conformational changes by a single α-helix peptide p37 dramatically increased gp96 binding to HER2 (gp96 Conformational Changes Inhibitor Inhibits HER2 Dimerization, PLOS ONE, April 2015; see abstract). The side chains and alpha helical structure required of this specifically designed inhibitor are integral to binding gp96, and changing the side chains of 40% of the peptide is not predictable with regard to binding capabilities, based on the disclosure of only one full length sequences. Without any other examples of peptides variants having this function, there is no support to establish the partial peptide structure needed to achieve this function.
(d) Representative number of examples
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.").
Applicants have provided only one example of a PIBC peptide that is 100% identical to SEQ ID NO: 1. Given this lack of description in the specification, the application fails to describe the claimed invention in such a full, clear, and concise and exact terms that a skilled artisan would recognize that applicants' were in possession of the genus of claimed invention.
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.
Claim(s) 1-5, 7, 8 and 11-14 are rejected under 35 U.S.C. 103 as being unpatentable over Kang Ming Hai (CN108864258; See ISR; herein after ‘Hai’) in view of DeNardo et al. (Clinical Cancer Research, Vol. 9, 3854s–3864s, September 1, 2003; see abstract, p. 3862s, Col. 2 and Fig. 4).
Hai teaches a PIBC polypeptide, SEQ ID NO: 1, which is identical to the SEQ ID NO: 1 of instant claim 1 (p. 1 of google patents translation; abstract, claim 1). This reference also teaches a derivatized polypeptide with the same function, obtained by substitutions, deletions, and/or addition of one or more amino acid residues (p. 1 of translation, claims 1-5). The modification is achieved by the Michael addition reaction of a compound A and a compound B (See p. 1 of translation; abstract). This reference also teaches that compound A is a PEG with one terminus modified by maleimide, compound B is a PIBC with an N or C terminus substituted or added cysteine residues, and the structural formula of the compound A is as shown in formula V, which is the same as formula II in the present application (p. 1 of translation, claim 5). This reference also discloses a preparation method for the PEGylated polypeptide, using a compound A and a compound B to carry out a Michael addition reaction to obtain the PEGylated polypeptide, which applies the PEGylated polypeptide in a composition for binding to gp96 protein and product for treating or preventing diseases caused by the gp96 protein (p. 1 of translation). This reference further teaches that the PEG-peptide is for inhibiting tumor cell proliferation, growth and invasion, which can be used as a pharmaceutical formulation for promoting tumor cell apoptosis and inhibiting tumors (p. 1-3 of translation, claims 7-10).
The difference between the prior art and the instant claims is that the prior art does not teach that the average molecular wight of the PEG is 20000-40000.
DeNardo teaches that teaches that as PEGylated peptide molecular size increases, blood and body clearances decreased and that the effect of molecular size on blood clearance was not altered by ligand binding specificity with t1/2 ranging from 5.4 h with PEG40000 to 17.7 h with PEG150000. This reference concludes that the use of PEG polymers combined with high-affinity tumor cell binding ligands offers a flexible approach to optimize the molecular size and structure of PEG for enhanced tumor delivery, tumor binding, and normal tissue clearance, as part of tumor targeting drug development (p. 3862s, Col. 2).
It would have been obvious to one of ordinary skill in the art at the time of the invention to have conjugated the larger MW PEG of DeNardo to the PIBC peptide of Hai because DeNardo teaches that the clearance rate decreases with increasing PEG molecular weight, making optimizing molecular weight of PEG a flexible approach for enhanced tumor delivery. One would be motivated to do so in the tumor inhibiting PIBC peptide of Hai because DeNardo demonstrates that half-life increases for tumor treating peptides, ligand specificity for the peptides has little effect on clearance, and increasing PEG molecular size improves clearance and delivery. As such, there is a reasonable expectation of success that the peptide of Hai can be conjugated to a larger PEG of DeNardo to improve half-life, enhance tumor delivery/binding and retain function.
This meets the limitations of claims 1 and 2 because Hai teaches a PIBC conjugated to PEG and DeNardo provides motivation to use higher molecular weight PEG to increase half-life. Claims 3 and 4 are met because Hai teaches the same Michael reaction with PEG and the cysteine of PIBC, and DeNardo provides motivation to increase the polymerization variable “n.” Claims 7 and 8 are met because Hai clearly teaches pharmaceutical formulations for treating breast cancer (e.g., see p.8 of translation). Claim 11 is met because Hai teach linear PEG (see e.g., claim 5). Claim 12 is met because the same basic structure is taught because all of the variables are merely exemplary (reciting “R is the end group, such as methoxy,” “linking group, e.g.,” and “e.g., cysteine”), rendering the claim unclear as to whether these are required limitations as they are exemplary, not clearly required. Furthermore, Hai also teaches these limitations for formulas II-V. Claim 13 is met because Hai teaches the same PIBC-PEG and DeNardo provides motivation to increase the MW via the “n” variable. Claim 14 is met because the elected group is drawn to the product itself, and not the process of making the product. As such, the structure of the reactant and the steps taken to provide the final product are not the determinants of product patentability.
MPEP 2113 states: "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted) (Claim was directed to a novolac color developer. The process of making the developer was allowed. The difference between the inventive process and the prior art was the addition of metal oxide and carboxylic acid as separate ingredients instead of adding the more expensive pre-reacted metal carboxylate. The product-by-process claim was rejected because the end product, in both the prior art and the allowed process, ends up containing metal carboxylate. The fact that the metal carboxylate is not directly added, but is instead produced in-situ does not change the end product.). Furthermore, "[b]ecause validity is determined based on the requirements of patentability, a patent is invalid if a product made by the process recited in a product-by-process claim is anticipated by or obvious from prior art products, even if those prior art products are made by different processes." Amgen Inc. v. F. Hoffmann-La Roche Ltd., 580 F.3d 1340, 1370 n. 14, 92 USPQ2d 1289, 1312, n. 14 (Fed. Cir. 2009). See also Biogen MA Inc. v. EMD Serono, Inc., 976 F.3d 1326, 1334, 2020 USPQ2d 11129 (Fed. Cir. 2020) ("Biogen is certainly correct that the scope of composition and method of treatment claims is generally subject to distinctly different analyses. But where, as here, the novelty of the method of administration rests wholly on the novelty of the composition administered, which in turn rests on the novelty of the source limitation, the Amgen analysis will necessarily result in the same conclusion on anticipation for both forms of claims.").
As such, the final product, a PIBC peptide linked to a PEG20000-40000 is rendered obvious by the art, regardless of the process by which it is made.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANETTE M LIEB whose telephone number is (571)270-3490. The examiner can normally be reached M-F 10-7.
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/JEANETTE M LIEB/Primary Examiner, Art Unit 1654
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