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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 28, 2025 has been entered.
Claim Status
The claim set and Applicant’s remarks filed July 28, 2025 have been entered. Claims 1-14, 16-18 and 24 are canceled. Claim 35 is new. Thus, claims 15, 19-23 and 25-35 as amended are examined on the merits herein.
Withdrawn Objections and Rejections
With respect to the objections and/or rejections mailed in the final office action on March 31, 2025:
(I) The objection to claim 21 is withdrawn in view of Applicant’s amendment to the claim.
Although, the Examiner respectfully notes within the current claim set under examination Applicant has now canceled claim 16 and has incorporated those limitations as an amendment to claim 15 on pg. 6, lines 1-7 from the bottom of the page.
Thus, the Examiner respectfully notes in view of the amendment discussed above a new 112(b) rejection based on a lack of antecedent basis has been made and discussed in further detail below.
(II) The rejection of claims 15-34 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is withdrawn in view of Applicant removing the limitation “preventing and/or” from claim 15, line 1.
Response to Arguments
(I) The rejection of claims 15, 20-23, 25 and 29-32 under 35 U.S.C. 103;
(II) The rejection of claims 15, 19 and 28 under 35 U.S.C. 103;
(III) The rejection of claim 26 under 35 U.S.C. 103; and
(IV) The rejection of claims 27 and 33-34 are rejected under 35 U.S.C. 103; are maintained.
Applicant argues:
(A) The amended claims recite a ratio of the number of the repeating unit which includes the cholesteryl group to the number of the disaccharide repeating units present in the hyaluronic acid is 20 to 50%, that is, the cholesteryl group introduction ratio is limited to 20 to 50%.
Thus, the ratio of carboxylic acids which do not have a cholesterol group within the claimed hyaluronic acid derivative is 50 to 80%. See Applicant’s remarks, pg. 22, Claim Rejections under 35 U.S.C. 103, paragraph 3.
(B) Shiku discloses that the carboxylic acid introduction rate is 27%, See Fig.4 in paragraph [0068]. Thus, the ratio or carboxylic acids in the hyaluronic acid derivative of the amended claim 15 is significantly higher than that of the CHP-COOH of Shiku; and as such the claimed hyaluronic acid derivative which has a high ratio of carboxylic acid is likely to become ionic, even after a complex of a hyaluronic acid derivative and an antigen is formed, see Applicant’s remarks, pg. 22, last two paragraphs of the page – pg. 23, first paragraph of the page.
(C) Shiku in view of Nakai does not disclose the amended subject matter discussed in argument (B) discussed above, see Applicant’s remarks, pg. 23, first paragraph.
(D) Akiyoshi fails to make up for the deficiencies of Shiku and Nakai discussed in arguments (A)-(C) discussed above, see Applicant’s arguments, pg. 23, paragraph 5.
(E) Nezafat fails to make up for the deficiencies of Shiku and Nakai discussed in arguments (A)-(C) discussed above, see Applicant’s arguments, pg. 24, paragraph 2.
(F) Callahan fails to make up for the deficiencies of Shiku and Nakai discussed in arguments (A)-(C) discussed above, see Applicant’s arguments, pg. 24, paragraph 5.
With respect to Applicant’s arguments (A)-(F), the Examiner respectfully notes Nakai teaches a hydrophobic hyaluronic acid derivative of (a) Formula (I) which corresponds to the hyaluronic acid derivative of Formula (II) of claim 15; (b) Formula (II) which corresponds to the hyaluronic acid derivative of formula (III) of claim 15; and (c) Formula (IIb) which corresponds to the hyaluronic acid derivative of formula (IIIc) of claim 15.
Additionally, Akiyoshi teaches a hydrophobic hyaluronic acid derivative of Formula (I) which corresponds to the hyaluronic acid derivative of formula (I) of claim 15.
The Examiner further respectfully notes Nakai teaches the hyaluronic acid according to Formulas (I), (II) and (IIb) as discussed above wherein a percentage of the disaccharide unit comprising the group —NR9—Z1—Z2 in the existing disaccharide repeating units is 3 to 50%.
Moreover, the Examiner respectfully notes the group —NR9—Z1—Z2 corresponds to and is encompassed by X1 in Formula (I) and X2 in Formula (II) of Nakai and wherein Z2 is —NRb—COO—Z3, see Nakai, paragraph [0062]; Rb is H, see Nakai, paragraph [0074]; and Z3 is a steryl group, see Nakai, paragraph [0077], wherein steryl is defined as including a cholesteryl group, see Nakai, paragraph [0312].
Therefore, the Examiner respectfully notes the teachings of Nakai overlap with the cholesteryl group introduction ratio which is limited to 20 to 50% as discussed above and recited in the amendment to instant claim 15.
Furthermore, the Examiner respectfully notes the hyaluronic acid derivatives of Nakai would also have a ratio of carboxylic acids which do not have a cholesterol group to be 50 to 97%; which the Examiner respectfully notes is based on the 3 to 50% limitation discussed above when the disaccharide repeating unit comprises the group —NR9—Z1—Z2, wherein Z2 is —NRb—COO—Z3, and Z3 is a steryl group which again the Examiner respectfully notes Nakai defines to include a cholesterol group.
Thus, Applicant’s arguments (A)-(F) have been fully considered are not found persuasive.
Claim Objections
Claim 15 is objected to because of the following informalities:
Claim 15, pg. 6, line 9 and Claim 35, pg. 15, line 5 each recite “the hyaluronic acid having an introduced hydrophobic group further comprising”. The Examiner respectfully notes this is the second recitation of this limitation in each claim discussed above as the first recitation of this limitation is within claim 15, lines 2-3 and claim 35, lines 2-3, respectively.
Thus, to promote clarity the Examiner respectfully suggests replacing the word “an” recited immediately before the word “introduced” with the word “the” as discussed above.
Appropriate correction is required.
Claim Interpretation
(A) Claim 15 does not require any particular amount of the claimed vaccine formulation, thus any amount administered reads on the claim.
(B) Claim 35, line 1, recites “preventing” which includes a healthy subject, thus administering the claimed hyaluronic acid (HA) to any subject reads on the claim.
Claim Rejections - 35 USC § 112
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.
(I) Claim 35 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a cancer, does not reasonably provide enablement for preventing a cancer in a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a result, substantiation of utility and its scope is required when utility is speculative, sufficiently unusual or not provided, and enablement must be commensurate with the scope of the claim language. As MPEP § 2164.08 states, “The Federal Circuit has repeatedly held that "the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’." In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).”
As stated in MPEP § 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”.”
The applicant’s attention is drawn to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), where the court set forth eight factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. They are: (1) The nature of the invention; (2) The state of the prior art; (3) The level of skill in the art; (4) The
predictability or lack thereof in the art; (5) The breadth of the claims; (6) The amount of direction or guidance present; (7) The presence or absence of working examples; and (8) The quantity of experimentation needed.
It is noted that all of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
The nature of the invention: The invention is drawn to a method for preventing a cancer in a subject by administering the vaccine formulation as recited in claim 35.
The Examiner reasonably interprets the phrase “a cancer” to mean any cancer. Therefore, the method of preventing any cancer in a subject as required in claim 35 is accomplished by administering the vaccine formulation comprising a hyaluronic acid derivative having an introduced hydrophobic group as claimed and an antigen, wherein the antigen is an antigenic peptide or an antigenic protein as recited in claim 35.
Thus, in order to be enabled for the full scope of prevention one skilled in the art must reasonably be able to ascertain which agents are effective, obtain said agents, and successfully use said agents for preventing any cancer.
The state of the prior art: The state of the art does not recognize a vaccine formulation comprising a hyaluronic acid (HA) derivative in preventing a cancer. Attention is drawn to Lin et al. (Published 27 September 2021, pharmaceutics, Vol. 13, Issue 10, pp. 1-15, PTO-892 mailed 09/18/2024), which teaches hyaluronic acid-glycine-cholesterol conjugate-based nanoemulsion as a potent vaccine adjuvant for T-cell-mediated immunity, see title. Lin teaches a hyaluronic acid derivative called HACH similar to the structures of formulas (I), (II), (III) and (IIIc) as HACH contains a hyaluronic acid core, see pg. 6, figure 1(iii), HACH.
Lin teaches SQ@HACH significantly enhanced antigen-specific immune responses, including the polarization of IgG antibodies, the cytokine secretions of T cells, and enhancement of cytotoxic T lymphocyte (CTL) activation.
Moreover, SQ@HACH revealed lower local inflammation and rapidly absorbing properties compared with AlPO4 after intramuscular injection in vivo, indicating the potential functions of the HA-derived conjugate as an excipient in vaccine formulations for enhancement of T cell-mediated immunity. See abstract.
Lin teaches SQ@HACH has good potential as a candidate adjuvant for the development of vaccines against infectious diseases and cancer, see pg. 12, section 4, conclusion, paragraph 1.
Lin describes their HA-derivative as an excipient in vaccine formulations for enhancing T-cell mediated immunity and as a candidate adjuvant in developing vaccines against cancer. However, the Examiner respectfully notes that Lin does not demonstrate or even suggest that their HA-derivative can prevent any cancer.
Additionally, Shiku et al. (Published 30 October 2014, US-20140322344-A1, IDS filed 08/19/2021), which is referenced in the subsequent 103 rejections below, teaches a vaccine preparation for treating cancer by administering a complex of a hydrophobized polysaccharide and at least one synthetic long peptide derived from a tumor-specific antigenic protein and/or a pathogen-derived antigenic protein, see paragraph [0038].
Shiku exemplifies the hydrophobized polysaccharide as a cholesteryl pullulan (CHP) complexed with a tumor-specific antigenic protein known as MAGE-A4 p264:40; which was simultaneously subcutaneously administered with CpG oligo DNA into BALB/c mice having mouse colon cancer cells CT 26; and wherein the MAGE-A4 gene was stably introduced and subcutaneously implanted, see paragraph [0071].
Shiku further shows after administration of the complex and CpG DNA, the tumor area (mm2) was suppressed over the approximately 40-day observation period after tumor cell implantation, see Figure 7, right column.
Although, Shiku also teaches CHP complexed with a tumor-specific antigenic protein known as mERK2 p121:37 simultaneously subcutaneously administered with CpG oligo DNA into BALB/c mice; Shiki teaches prior to administration said mice were subcutaneously implanted with mouse fibrosarcoma cells CMS5a having mERK2 protein, see paragraph [0072].
Shiku further shows after administration of the complex and CpG DNA, the administration of said CHP and CpG oligo DNA initially slowed progression of the tumor area (mm2) but steadily increased in 4 out of the 5 mice tested and eventually exponentially increased in 3 out of the 5 mice tested during the approximately 30-day observation period after tumor cell implantation, see Figure 8, right column.
Moreover, Muraoka et al. (Published 02 September 2014, ACS Nano, Vol. 8, Issue 9, pp. 9209-9218, IDS filed 03/27/2025) teaches effects of vaccination on in vivo tumor growth in the prophylactic setting, where a CHP complexed with a mERK2 long peptide antigen (LPA) and CpG oligo DNA (ODN) was simultaneously subcutaneously injected into BALB/c mice following subcutaneous transplantation of CMS5a cells into mice at day 0, see pg. 9214, Figure 4. Muroka demonstrates in Figure 4a that the CHP:mERK2 LPA and CpG PDN did not suppress tumor volume (mm3), see pg. 9214, Figure 4a.
Muraoka also teaches a CHP complexed with a MAGE-A4 long peptide antigen (LPA) and CpG oligo DNA (ODN) simultaneously subcutaneously injected into BALB/c mice following subcutaneous transplantation of CT26/MAGE-A4 cells into mice at day 0, see pg. 9214, Figure 4. Muraoka demonstrates in Figure 4b that the CHP:MAGE-A4 LPA and CpG PDN did suppress tumor volume (mm3) in 7 out of the 7 mice tested over the 36-day observation period after tumor cell implantation, see pg. 9214, Figure 4b.
However, the Examiner also respectfully notes the word "prevention" as described according to the Centers for Disease Control and Prevention (page 1, PTO-892 mailed 09/18/2024) has three stages; (1) primary prevention is in intervening before health effects occur; (2) secondary prevention is screening to identify diseases in the earliest stages before the onset of signs and symptoms; and (3) tertiary prevention is managing disease post diagnosis to slow or stop disease progression, see CDC, prevention, pg. 1.
Furthermore, based on the teachings of Shiku and Muraoka, the Examiner respectfully notes the data disclosed by these reference are related to using a hydrophobic polysaccharide, specifically CHP, which is complexed with a tumor-specific antigenic protein or peptide, either MAGE-A4 or mERK2, in targeting specific cancer cell lines, for example CT26 cells or CMS5a cells respectively; that have either the MAGE-A4 gene or mERK2 protein respectively as demonstrated by Shiku or Muraoka.
The Examiner also respectfully notes when reviewing the Shiku reference, Shiku demonstrates suppression for only CHP complexed with a tumor-specific antigenic protein known as MAGE-A4 p264:40 in CT26 cells which specifically have the MAGE-A4 gene; while in CMS5a cells that have mERK2 protein no suppression was demonstrated. Additionally, these findings of Shiku as discussed above are supported by the data presented by Muraoka as discussed above.
Finally, the Examiner respectfully notes that within the therapeutic methods of Shiku and Muraoka as discussed above, both methods administered the CHP:antigenic protein or peptide simultaneously with CpG oligo DNA which the Examiner respectfully notes is not a required limitation recited by the Applicant within the method of prevention as recited in claim 35.
Therefore, it is not understood how the recited method for preventing any cancer with any antigenic peptide or antigenic protein, in light of the teachings of Lin, Shiku and Muraoka, provides the claimed prophylactic or preventive effect in a subject as interpreted by a skilled practitioner of the medical or pharmaceutical arts in what would be to reduce for long-term the occurrence of or to eliminate any cancer in a subject or to ensure said subject does not obtain any cancer by the claimed method.
Thus, in total, the actual use of hyaluronic acid derivatives comprising any antigenic peptide or antigenic protein for preventing any cancer in a subject in need thereof is currently unclear.
The relative skill in the art: The relative skill of those in the art is high.
The predictability or lack thereof in the art: As discussed above, the use of the claimed hyaluronic acid derivatives to prevent any cancer are unknown. As a result, at the time of the invention the field of therapies to prevent any cancer by administering the claimed hyaluronic acid derivatives were limited. Therefore, at the time of the invention the field of therapeutic use to prevent any cancer by administering the claimed hyaluronic acid derivatives was relatively underdeveloped and unpredictable.
The breadth of the claims: The breadth of the claim is extremely broad and is seen to encompass a method of preventing any cancer by administering a vaccine formulation that comprises the hyaluronic acid derivatives recited in claim 35, which the Examiner respectfully notes said derivatives comprise any antigenic peptide or antigenic protein.
The amount of direction or guidance present: The specification suggests a vaccine for use in the prevention of a cancer comprising a complex of hyaluronic acid derivative having an introduced hydrophobic group and an antigen, see paragraph [0001].
However, this suggestion is based on Applicant’s assertion that there are known antigens that have been demonstrated by either in vitro or in vivo experiments to prevent any cancer; and the additional assertion that the antigen can be complexed with the recited hyaluronic acid derivative. Thus, Applicant’s assertions are not fully supported by existing experimental results regarding preventing any cancer in a subject in view of the State of the Prior Art section above.
The presence or absence of working examples: Applicant’s specification provides mouse tumor growth tests for a mouse colorectal cancer cell CT26 cell line, see paragraph [0271] and results in figures 16-1 and 16-2, wherein figures 16-1 demonstrated lower tumor volume of the tested HA-derivatized conjugates in figure 16-1; and mouse melanoma B16F10, see paragraph [0273] and results in figures 17-1 and 17-2, wherein figure 17-1 demonstrated slower tumor volume growth between 0 and 28 days after inoculation of tumor cells, respectively.
The Examiner also respectfully notes within Figure 16-1 that the tumor volume steadily decreased between days 16-21 when BALB/c mice having the colorectal cancer cell line CT26 were administered with a therapy known as 99k43; wherein the specification notes 99k43 is a complex of the antigenic peptide AH1gp70-6L with the hyaluronic acid derivative known as 99k HA-C6-Chol-43% and also comprises CpG oligo DNA within the formulation, see specification, pg. 21, paragraph 3.
The Examiner also respectfully notes within Figure 17-1 that the tumor volume did not steadily decrease over the approximately 28-day observation period after tumor cell implantation when C57BL/6 mice having the melanoma B16F10 cell line were administered a complex of an HA derivative known as 99k HA-C6-Chol-43%, an antigenic peptide known as TRP2TRP gp100-6Y and CpG oligo DNA, see specification pg. 21, paragraph 5.
The Examiner further respectfully notes the data presented within Figures 16-1 and 17-1 of their corresponding experiments are not actual examples of preventing any cancer or reducing for the long-term the occurrence of any cancer in a subject.
Rather they are based on the extrapolation of a complex of the recited hyaluronic acid derivatives and the specific antigen tested that Applicant suggests may have a prophylactic or preventive effect on any cancer in a subject.
Finally, the Examiner also respectfully notes that within the therapeutic methods corresponding to Figures 16-1 and 17-1 discussed above also administer CpG oligo DNA within the formulation which the Examiner respectfully notes is not a required limitation recited by the Applicant within the method of prevention as recited in claim 35.
Note the lack of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art such as the use of hyaluronic acid derivatized antigenic protein conjugates on the prevention of any cancer in a subject.
The quantity of experimentation needed: In order to translate the suggestions in Applicants’ disclosure into an actual therapeutic model with the full range of all possible prevention methods beyond those known in the art, one skilled in the art would have to undertake a novel and extensive research program to show that a vaccine formulation comprising a hyaluronic acid derivative as recited in claim 35 could successfully prevent any cancer in a subject. Therefore, because this research would have to be exhaustive, and because it would involve such a wide and unpredictable scope of cancers wherein the method requires administering a hyaluronic acid derivative wherein the antigen is any antigenic peptide or antigenic protein, it would constitute an undue and unpredictable search and experimental burden.
Genentech, 108 F.3d at 1366, states that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion.” And “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Therefore, in view of the Wands factors, as discussed above, particularly the state of the art and the lack of guidance or working examples, Applicants fail to provide information sufficient to practice the claimed invention of a method of preventing any cancer in a subject comprising administering the vaccine formulation as recited in claim 35.
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.
(II) Claims 21 and 25-26 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.
(a) Claim 21 recites the limitation "the hyaluronic acid has a weight-average molecular weight of 5 kilodaltons to 200 kilodaltons" in lines 4-5. There is insufficient antecedent basis for this limitation in the claim. Claim 21 depends from canceled claim 16, thus canceled claim 16 does not provide proper antecedent basis for claim 21.
In the interest of compact prosecution, the Examiner will interpret claim 21 depends from claim 15 which the Examiner respectfully notes said limitation discussed above is a narrower version of the limitation present in claim 15, pg. 7, lines 8-9.
(b) Claim 25 recites the limitation "the antigenic peptide comprises as recited" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 25 depends from canceled claim 24, thus canceled claim 24 does not provide proper antecedent basis for claim 25.
Claim 26 is included in this rejection as it depends from claim 25.
In the interest of compact prosecution, the Examiner will interpret claim 25 depends from claim 15 which first recites the limitation of “an antigenic peptide” as required in claim 15, pg. 7, line 10.
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 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.
(I) Claims 15, 20-23, 25 and 29-32 are rejected under 35 U.S.C. 103 as being unpatentable over Shiku et al. (Published 30 October 2014, US-20140322344-A1, IDS filed 08/19/2021) in view of Nakai et al. (Published 20 August 2015, US-20150231268-A1, IDS filed 08/19/2021).
Regarding claims 15, 20-23, 25 and 29-32, Shiku teaches a vaccine preparation for treating cancer includes a complex of a hydrophobized polysaccharide and at least one synthetic long peptide derived from a tumor-specific antigenic protein and/or a pathogen-derived antigenic protein (e.g. the antigenic peptide or antigenic protein required in claim 15, pg. 7, line 10). The at least one synthetic long peptide contains at least one CD8+ cytotoxic T-cell recognition epitope and at least one CD4+ helper T-cell recognition epitope. The complex is simultaneously administered to the patient with at least one immunopotentiating agent. See abstract.
Shiku teaches the synthetic long peptide is preferably a polypeptide including 23-40 amino acids that include at least two or more T-cell recognition epitopes, see paragraph [0038].
Shiku teaches immunopotentiating agents (adjuvants) have been conventionally used in order to enhance the immunogenicity of vaccines. A variety of substances derived from bacteria and viruses, for example, nucleic acids (DNA and RNA), proteins, lipopolysaccharides and the like, have been used as immunopotentiating agents, i.e. where the adjuvant is a substance activating an innate immune receptor (pattern recognition receptor), required in claim 23 and claim 29. See paragraph [0013].
Although, Shiku does not teach the hyaluronic acid derivative having (a) formula (II), required in claims 15 and 20, or formula (III), required in claim 15; and (b) formula (IIIc), required in claim 21.
However, in the same field of endeavor of polysaccharide derivatives, Nakai teaches, with respect to limitation (a), (1) a hyaluronic acid derivative comprising a repeating unit represented by formula (I),
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, see paragraph [0052], which is the same structure as formula (II) of claim 15, see paragraphs [0053]-[0079], including where X1, which corresponds to X1a in formula (II) is hydroxy, C1-6 alkoxy, —O−Q+, —NR7R8, or —NR9—Z1—Z2, see paragraph [0055]; wherein R9 is a hydrogen atom or a C1-6 alkyl, see paragraph [0057]; Z1 is C2-30 alkylene, see paragraph [0059]; Z2 is —NRb—COO—Z3, see paragraph [0062]; Rb is H, see paragraph [0074]; and Z3 is a steryl group, see paragraph [0077], wherein steryl is defined as including a cholesteryl group, see paragraph [0312], required in instant claims 15 and/or 20. Nakai teaches by using a hyaluronic acid of the present invention, a sustained release preparation containing a large amount of a drug, in particular, a low molecular weight compound or a protein or a peptide having an efficacy while maintaining its bioactivities can be provided, see paragraph [0103].
Nakai also teaches wherein if the hyaluronic acid derivative comprises no repeating units represented by formula (I), in which X1 is —NR9—Z1—Z2, then the hyaluronic acid derivative further comprises a repeating unit represented by formula (II),
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, see paragraph [0080], which the Examiner respectfully notes is the same structure as formula (III) of claim 15, see paragraphs [0081]-[0084].
Nakai also teaches, with respect to limitation (b), (2) the hyaluronic acid derivative according to the above (1) corresponding to formula (I) previously discussed, see paragraph [0052], further comprising a repeating unit represented by formula (IIb),
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, see paragraph [0084], which is the same structure as formula (IIIc) of claim 16, see paragraphs [0085-[0087], including formula (IIb) referring to the weight-average molecular weight of the hyaluronic acid, where R1b, R2b, R3b, and R4b are all hydrogen atoms; R5b is acetyl (e.g. a C1 alkylcarbonyl); and Xb is —O−Na+ in formula (IIb), see paragraph [0342], where the weight-average molecular weight of hyaluronic acid (including a salt thereof) exclusively composed of the disaccharide unit represented by formula (IIb) used as a starting material is preferably 1 kDa to 2000 kDa, see paragraph [0341], required in claim 15.
Nakai teaches (7) the hyaluronic acid wherein a sum of percentages of the repeating unit represented by formula (I) and the repeating unit represented by formula (II) in existing disaccharide repeating units is 70 to 100% (e.g. 80% or more of disaccharide repeating units in the hyaluronic acid derivative is a repeating unit selected from the repeating units represented by the formula (II), the formula (III) and the formula (IIIc), required in claim 15, pg. 7, lines 2-5, see paragraph [0092].
Nakai teaches wherein the hyaluronic acid derivative is produced by using hyaluronic acid exclusively consisting of the disaccharide unit represented by formula (IIb) according to (2) and has a weight average molecular weight of 3 kilo Daltons to 1,500 kilo Daltons when R1b, R2b, R3b, and R4b are all hydrogen atoms; R5b is acetyl, and Xb is —O−Na+ (e.g. the hyaluronic acid derivative, required in claim 15, pg. 7, lines 6-9), see paragraph [0093].
Nakai teaches (5) the hyaluronic acid according to any of the above (1) to (4), wherein a percentage of the disaccharide unit comprising the group —NR9—Z1—Z2 in existing disaccharide repeating units is 3 to 50% (e.g. the ratio of the number of repeating units which includes the cholesteryl group to the number of the disaccharide repeating units present in the hyaluronic acid derivative, required in claim 15, pg. 7, lines 11-13), see paragraph [0090].
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have substituted the hydrophobized polysaccharide of Shiku for the hyaluronic acid derivatives of formula (I), (II) and (IIb) as taught by Nakai as within the scope of the artisan as combining prior art elements according to known compounds to yield predicable results. One of ordinary skill in the art would have been motivated to make this substitution to create the hydrophobized polysaccharide of Shiku.
One of ordinary skill in the art would have had a reasonable expectation of success to have made the substitution as described above as Nakai teaches a sustained release preparation containing a large amount of a drug, in particular, a low molecular weight compound or a protein or a peptide having an efficacy while maintaining its bioactivities can be provided.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teaching of the prior art.
(II) Claims 15, 19 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Shiku et al. (Published 30 October 2014, US-20140322344-A1, IDS filed 08/19/2021) and Nakai et al. (Published 20 August 2015, US-20150231268-A1, IDS filed 08/19/2021) as applied to claims 15, 20-23, 25 and 29-32 above, and further in view of Akiyoshi et al. (Published 01 September 2011, US-20110212901-A1 IDS filed 08/19/2021).
Shiku and Nakai address claims 15, 20-23, 25 and 29-32 as written above. Although, Shiku does not teach the hyaluronic acid derivative having formula (I), required in claims 15, 19 and 28.
However, in the same field of endeavor of polysaccharide derivatives, Akiyoshi teaches a hydrophobic group-introduced hyaluronic acid derivative comprising at least one repeating unit represented by the formula (I),
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, which is the same structure as formula (I) of claim 15, see paragraphs [0061]-[0082], where R5 of formula (I) in claim 15 is an acetyl group as shown above (e.g. a C1 alkylcarbonyl); and includes where Z is a direct bond, see paragraph [0062], Y is C2-30 alkylene or –(CH2CH2O)m-CH2CH2, see paragraph [0078], wherein m is an integer of 2 to 100, see paragraph [0082]; X1 is —NRb—COO—R, see paragraph [0065]; Rb is H, see paragraph [0075]; and R is a steryl group, see paragraph [0077], wherein steryl group is defined to include a cholesteryl group, see paragraph [0242], required in claims 15, 19 and 28; and R1, R2, R3 and R4 are each independently selected from a hydrogen atom, C1-6 alkyl, formyl and C1-6 alkyl carbonyl, see paragraph [0061].
Akiyoshi teaches the hydrophobic group-introduced hyaluronic acid derivative defined herein wherein an introduction ratio of hydrophobic groups relative to disaccharide repeating units present in the derivative is 7 to 42%, see paragraph [0126].
Akiyoshi teaches a hyaluronic acid derivative in which a particular hydrophobic group is introduced associates spontaneously in an aqueous solution while encapsulating a large amount of a drug, especially a pharmacological active protein or peptide, see paragraph [0058].
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have substituted or included the hydrophobized polysaccharide of Shiku for the hyaluronic acid derivatives of formula (I) as taught by Akiyoshi as within the scope of the artisan as combining prior art elements according to known compounds to yield predictable results. One of ordinary skill in the art would have been motivated to make this substitution to create a hydrophobized polysaccharide as taught by Shiku.
One of ordinary skill in the art would have had a reasonable expectation of success to have made the substitution or addition as described above as Akiyoshi teaches a hyaluronic acid derivative in which a particular hydrophobic group is introduced associates spontaneously in an aqueous solution while encapsulating a large amount of a drug, especially a pharmacological active protein or peptide.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teaching of the prior art.
(III) Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Shiku et al. (Published 30 October 2014, US-20140322344-A1, IDS filed 08/19/2021) and Nakai et al. (Published 20 August 2015, US-20150231268-A1, IDS filed 08/19/2021) as applied to claims 15, 20-23, 25 and 29-32 above, and further in view of Nezafat et al. (Published 7 February 2014, Journal of Theoretical Biology, Vol. 349, pp. 121-134, PTO-892 mailed 09/18/2024).
Shiku and Nakai address claims 15, 20-23, 25 and 29-32 as written above. Shiku teaches preparing long peptides that simultaneously contain recognition epitopes of killer T cells and helper T cells for maximizing therapeutic effects on cancers, see paragraph [0036].
Although, Shiku does not teach wherein the antigenic peptide has an amino acid linker between the epitopes, required in claim 26.
However, in the same field of endeavor of multiepitope peptide vaccines, Nezafat teaches a novel multi-epitope peptide vaccine against cancer: an in silico approach, see title. Nezafat teaches the vaccine consists of three major sections: toll-like receptor 4 ligand, CD8+ and CD4+ T cells epitopes and each section was joined together by appropriate linkers, see pg. 121, highlights. Nezafat teaches each peptide segment that was derived from helper antigen, main antigens and TLR agonist were linked together by proper amino acid linkers, see pg. 123, left column, section 2.1, paragraph 1, and a schematic diagram of vaccine construct with amino acid linkers and CD8+ and CD4+ T cells epitopes was provided, see pg. 127, Fig. 2. Nezafat teaches a schematic diagram of vaccine construct with amino acid linkers and CD8+ and CD4+ T cells epitopes, see pg. 127, Fig. 2
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have included the amino acid linker of Nezafat between the CD8+ and/or CD4+ epitopes as taught by Shiku as within the scope of the artisan as combining prior art elements according to known compounds to yield predictable results. One of ordinary skill in the art would have been motivated to prepared long peptides that simultaneously contain recognition epitopes of killer T cells and helper T cells to maximize therapeutic effects on cancers as taught by Shiku above.
One of ordinary skill in the art would have had a reasonable expectation of success to have included the modification as stated above as Nezafat teaches a schematic diagram of a vaccine construct with amino acid linkers and CD8+ and CD4+ T cells epitopes.
Thus, the claimed invention as a whole would have prima facie obvious over the combined teaching of the prior art.
(IV) Claims 27 and 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over Shiku et al. (Published 30 October 2014, US-20140322344-A1, IDS filed 08/19/2021) and Nakai et al. (Published 20 August 2015, US-20150231268-A1, IDS filed 08/19/2021) as applied to claims 15, 20-23, 25 and 29-32 above, and further in view of Callahan et al. (Published 10 May 2013, Journal of Leukocyte Biology, Vol. 94, Issue 1, pp. 41-53, PTO-892 mailed 09/18/2024).
Shiku and Nakai address claims 15, 20-23, 25 and 29-32 as written above. Although, Shiku does not teach (a) administered in combination with at least one type of antibody for use in cancer treatment, required in claim 27; (b) wherein the antibody is an antibody inhibiting an immunosuppressive signal from a tumor, required in claim 33; and (c) wherein the antibody is an anti-CTLA-4 or an anti-PD1 antibody, required in claim 34.
However, in the same field of endeavor of cancer treatment, and with respect to limitations (a)-(c), Callahan teaches CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy, see title. Callahan teaches exemplified by the recently FDA-approved agent, ipilimumab, an antibody that blocks the coinhibitory receptor CTLA-4; and agents that target a second coinhibitory receptor, PD-1, or its ligand, PD-L1, are in clinical development, see abstract. Callahan teaches in one study of 15 patients with metastatic melanoma treated with ipilimumab, five of eight (62.5%) with tumor shrinkage or stabilization had developed NY-ESO-1 antibodies, see pg. 46, candidate biomarkers of response, paragraph 3. Callahan teaches a combination of ipilimumab at a dose of 3 mg/kg with a peptide vaccine, see pg. 42, right column, paragraph 2
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have included an anti-CTLA-4 antibody, exemplified by ipilimumab as taught by Callahan as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to simultaneously administer the complex to the patient with at least one immunopotentiating agent as taught by Shiku. One of ordinary skill in the art would have had a reasonable expectation of success to have included the addition as stated above as Callahan teaches a combination of ipilimumab at a dose of 3 mg/kg with a peptide vaccine.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teaching of the prior art.
Conclusion
No claims are allowed in this action.
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/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691