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 .
Remark
The response and amendment filed on 7/31/2026 have been acknowledged.
Claims 33, 38-44, 46-47, 49-56.60 and 62-67 have been amended. New claims 68-69 have been added. Claims 33, 38-44, 46-47, 49-56, 60, 62-69 are pending and considered.
Claim Rejections - 35 USC § 112
The rejection Claims 33, 38, 40-56, 60, 62, 66 and 67 under 35 U.S.C. 112 (a) or 35 U.S.C. 112 (pre-AIA ), first paragraph for the scope of enablement has been removed based on the amendment and percussive argument.
The rejection of Claims 33, 38, 40--56, 60-62, 66 and 67 under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. has been removed based on the amendment and percussive argument.
Claim Rejections - 35 USC § 102
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.
Claim(s) 33, 38-42, 47-54, 56, 60, 62-64, 65-67 are still under 35 U.S.C. 102 (a) (1) as being anticipated by Yang et al. (Nanoscale, 2016, Vol. 8, pp. 11543-11558), which is substantiated by Chen et al. (J. Hematol. Oncol. 2018, May 10, Vol. 11; 64, pp. at doi: 10.1186/s13045-018-0605-5.) or Kim et al. (Journal of polymer published on Oct. 12, 2018, 10(10), 1133; https://doi.org/10.3390/polym10101133).
In response, Applicants traverse the rejection and submit that the HA molecule is not chemical bound to the Her2 antigen rather through the binding to the CD44 receptor binding.
Applicants’ argument has been respectfully considered; however, it is not found persuasive for the following reasons.
CD44 is a protein with antigenic property, overexpression of CD44 is found in many cancer tumor cells. Therefore, CD44 overexpression or mutations are considered to be associated with cancer development and progression as evidenced by Chen et al.
Chen et al. teach that CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer development and progression. Hyaluronan, the main ligand for CD44, binds to and activates CD44 resulting in activation of cell signaling pathways that induces cell proliferation, increases cell survival, modulates cytoskeletal changes, and enhances cellular motility. The different functional roles of CD44 standard (CD44s) and specific CD44 variant (CD44v) isoforms are not fully understood. CD44v contains additional peptide motifs that can interact with and sequester growth factors and cytokines at the cell surface thereby functioning as coreceptors to facilitate cell signaling. Moreover, CD44v were expressed in metastasized tumors, whereas switching between CD44v and CD44s may play a role in regulating epithelial to mesenchymal transition (EMT) and in the adaptive plasticity of cancer cells. Here, we review current data on the structural and functional properties of CD44, the known roles for CD44 in tumorigenicity, the regulation of CD44 expression, and the potential for targeting CD44 for cancer therapy.
Therefore, CD44 is considered as a receptor associated to be related to a cancer associated protein, which is over expressed in many cancers or tumors cells. As a protein, it also has antigen property, or it can be also considered as an over-expressed or mutated self-antigen by the host cancer or tumor cells. The binding between CD44 and HA is via a chemical bound.
Furthermore, the MWs of the HA used for the treatment are 60kDa , 100kDa and 200kDa (See Section of Synthetic of AHNP-HAD. Moreover, The cytolytic effects that specifically lysis the cancer cells that over-expressing CD44 by the cancer or tumor cells also meet the limitation of the anti-specific by considering the CD44 as one of the cancer or tumor development or progression closely related antigen, which is well known and accepted by the state of art of cancel biology, wherein the peptide cancer cell specific T cell cytotoxic effect is only cited as one of option in the claims.
Regarding the newly added limitaiton that upon binding to the Cd44 positive cancer or tumor cells, the conjugated HA lead the cancer cell specific lysis , which is inherently taught by Yang et al. and also as evidenced by expertise, such as Kim et al.
Kim et al. teach that HA is a large hydrophilic biopolymer of repeating disaccharide units, and it can be directly conjugated to drugs. Direct conjugation of HA to anticancer drugs generates new compounds with promising antitumor effects. Such simple yet effective NP formulations can be used to improve treatment efficacy because HA-targeted receptors (CD44) are overexpressed in many cancers. Aside from this targeting ability, drug-conjugated HA provides merits in terms of increasing circulation time, drug stability, solubility, and cancer-targeting ability. Once internalized, drug-conjugated HA is hydrolyzed by intracellular enzymes and releases the drug to the target cell. Then the tumor and cancer cell specific lysis occurs. For example, Kim explains further that “Most cancer patients undergo a combination therapies including surgery, chemotherapy, and/or radiation treatment. Recently, targeted chemotherapy, gene delivery, and immunotherapy strategies are being tested in translational and clinical research. HA-based nanomaterials are effective in many cancer treatments. Several groups have reported attractive outcomes in vitro and preclinical studies about targeting drug-loaded NP with HA polymer [53]. Conjugating drugs with HA enhances the nanocarrier affinity and it enhances great tumor cell targeting ability via the HA–CD44-mediated endocytosis.
It is worth to note that the interaction between the hyaluronic acid and CD44 is considered via a chemical bond type of integration as evidenced by Helena Kellett-Clarke et al. (PLOS ONE, DOI:10.1371/journal.pone.0138137 September17,2015, pages 1-18).
To this context, the rejection is maintained.
New Ground of rejections:
Claim Rejections - 35 USC § 112
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
The term “derived” in claims 33, 39, 50, 60 and 66-68 is a relative term which renders the claim indefinite. The term “derived” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Please amend claims to overcome the rejection.
Claim 33 is vague and unclear for citing that the hyaluronic acid (HA) is an immunological adjuvant and has a molecular weight ranging from greater than 100 KDa to 500 KDa. Please clarify if the molecule weight of the HA is within the range of 100 KDa to 500 KDa or greater than the range of 100 KDa to 500 KDa. For instance, is 600kDa, which is great than the range between 100 to 500 kDa , is entitled? Or 200 kDa, which is great than the 100kDa also intitled?
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) 33, 38-42, 46, 47, 49, 50-54, 56, 60, 62--65, and 67-69 are rejected under 35 U.S.C. 103 as being unpatentable over US Application No. 20030049253A1 by Li et al.
The rejected claim 33 is directed to a method for producing an antigen-specific immune response against a tumor or cancer, comprising vaccinating a patient with a therapeutically effective dose of a vaccine comprising hyaluronic acid chemically bound to an antigen, wherein the hyaluronic acid is an immunological adjuvant and has a molecular weight ranging from greater than 100 KDa to 500 KDa, wherein the antigen is expressed by cells of the tumor or cancer or is an immunogenic peptide derived from an antigen expressed by cells of the tumor or cancer and wherein the vaccination elicits an antigen-specific cell-mediated immune response directed against cells of the tumor or cancer expressing the antigen or the antigen from which the immunogenic peptide is derived. Further , claim 38 cites that the antigen chemically bound to the hyaluronic acid is a protein-based or a peptide-based antigen.
The cited reference by Li et al. present inventions related to methods and compositions for modulation of an immune response to an antigen by modulation of presentation to T cells of epitopes of that immunogen by Major Histocompatibility Complex (MHC) molecules. More particularly, the invention provides immunogenic conjugates of polymers, such as hyaluronic acid and analogues thereof, and peptides or other molecules comprising epitopes recognized by MHC molecules, which conjugates are useful for modulating, that is, enhancing or diminishing, an immune system response to such epitopes (The 1st para.of the disclosure of the cited reference).
Further, the cited reference at para. [0071] teaches that present invention includes methods for making and using peptide vaccine compositions for preventing or treating disease in a mammal, preferably a human subject, which offer improved humoral and cell-mediated immune responses to a peptide consequent to covalent linkage of the peptide to a hyaluronic acid polymer or analogue thereof. The cell-mediated response to disease-associated antigens is known to play a critical role in preventing or eradicating, for example, infectious diseases and cancers.
Still further regarding Cancer-Associated Epitopes: they are genes products expressed or over expressed by at least one mutated gene, such as the epitopes of melanoma antigens including MAGE-3, MAGE-3(161-169), tyrosinase-related protein 2 (TRP2) epitopes (Para. 018)., CEA, 17-1 A, B-72.3 and Ep-CAM. (0119); Oncoprotein antigens such as p53 (0120) and even Epitopes of breast cancer antigens including HER2/neu (p 185) (0121); ovarian cancer related B cell epitopes [0122] as well as Other tumor antigens including T cell epitopes include BAGE, CAGE-1, CAGE-R, MUM-1, CDK4.
Regarding molecular weight of hyaluronic acid (HA) that is capable of being chemically covalently conjugated with an antigen, the cited reference teaches that Hyaluronic acid (HA; also known as “hyaluronan”) is a ubiquitous extracellular matrix (ECM) component, present at high concentrations in the skin, where it is synthesized primarily by dermal fibroblasts and by epidermal keratinocytes. Oligosaccharides of hyaluronan are potent activators of dendritic cells. In normal skin, HA exists as a high molecular weight (600,000-1,000,000 Daltons) (HMW-HA) nonsulfated glycosaminoglycan (GAG) composed of repeating units of D-glucuronic acid-N-acetyl-D-glucosamine. Functional properties of HMW-HA are the maintenance and hydration of the cutaneous ECM, as well as the binding of various growth factors and smaller GAGs with specificity for cellular receptors, termed hyaladherins.
In the section of DETAILED DESCRIPTION OF THE INVENTION, such as paragraph [0071], Li et al. teach that :” The present invention includes methods for making and using peptide vaccine compositions for preventing or treating disease in a mammal, preferably a human subject, which offer improved humoral and cell-mediated immune responses to a peptide consequent to covalent linkage of the peptide to a hyaluronic acid polymer or analogue thereof. The cell-mediated response to disease-associated antigens is known to play a critical role in preventing or eradicating, for example, infectious diseases and cancers. By improving the in vivo presentation of disease-associated antigens via covalent linkage to hyaluronic acid polymers and analogues thereof, the peptide vaccines of the present invention induce a significantly stronger cell-mediated immune response against the disease than free antigen or compositions with antigen simply mixed in HA polymer analogues. The present invention succeeds in inducing the desired specific and strong cell-mediated response in a mammal, which is central in preventing or treating the disease.
In [0074], the cited reference further teaches that :” The present invention also provides for peptide vaccines comprising a plurality of peptides conjugated to HA polymer analogues. Multi-peptide HA polymer analogue compositions may be prepared according to the methods detailed below wherein at least two distinct peptides are separately conjugated to an HA polymer analogue and then combined, or alternatively, at least two distinct peptides are combined prior to the conjugation step.”
Regarding the HA used as a carrier either conjugated or non-conjugated, the cited reference at paragraph [0044] teaches that:” More recently, effects of HA on antigen presenting cells (APCs) have been investigated. To determine the effects of HA on DC, HA fragments of different size were established. Only small HA fragments of tetra- and hexasaccharide size (sHA), but not of intermediate size (m.w. 80,000-200,000) or high m.w. HA (m.w. 600,000-1,000,000) induced immunophenotypic maturation of human monocyte-derived DC. Likewise, only sHA increased DC production of the cytokines IL-1β, TNF-α, and IL-12 as well as their all stimulatory capacity. These effects were highly specific for sHA, because they were not induced by other glycosaminoglycans such as chondroitin sulfate or heparan sulfate or their fragmentation products. sHA-induced DC maturation was shown not to involve the HA receptors CD44 or the receptor for HA-mediated motility, because DC from CD44-deficient mice and wild-type mice both responded similarly to sHA stimulation, whereas the receptor for HA-mediated motility is not detectable in DC. According to the authors, these findings suggest that during inflammation, interaction of DC with small HA fragments induces DC maturation.
However, at paragraph [0074], the cited reference teaches that “The present invention also provides for peptide vaccines comprising a plurality of peptides conjugated to HA polymer analogues. Multi-peptide HA polymer analogue compositions may be prepared according to the methods detailed below wherein at least two distinct peptides are separately conjugated to an HA polymer analogue and then combined, or alternatively, at least two distinct peptides are combined prior to the conjugation step. If the small molecular HA, (sHA) is less than 80.000 , the Multi-peptide HA polymer analogue of HA with 2 or more HA molecular would be within the range around as it claims from 100kDa to 500, kDa (See [0132-0138] and claims 1-12).
At paragraph [0096], the cited reference also teaches that The compositions of the present invention may be administered by subcutaneous, transdermal, intradermal, intramuscular, intraocular, intrarectal, sub-buccal, oral, nasal, or intra-aural administration or by inhalation preparations. Single or multiple administrations of the compositions can be carried out with dose levels and pattern being selected by the treating physician. Doses of any given peptide needed to obtain the desired immune response using the invention conjugates would typically be comparable to or less than described for an immunogenic dose of the same peptide formulated with a conventional adjuvant or carrier system.
To this context, it would have been obvious for a person with an ordinarily skilled in the art to be motivated by the cited reference to conjugated any cancer antigen including Her2 peptide antigen with a HA molecular with suitable molecule weight by the method clearly taught by the cited reference as a multimer of HA/cancer antigen as dimer or trimer or multimer with a reasonable expectation of success.
As there are no unexpected results have been provided, hence the claimed invention as a whole is prima facie obvious absence unexpected results.
Conclusion
Applicants’ 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 replying 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAO Q LI whose telephone number is (571)272-0904. The examiner can normally be reached M-F 8 am to 8 pm EST.
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BAO Q. LI
Examiner
Art Unit 1671
/BAO Q LI/Primary Examiner, Art Unit 1671
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