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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/17/2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner. See attached copy of PTO-1449.
Status of Application
Applicants' arguments/remarks filed 02/17/2026 are acknowledged. Claim(s) 1, is/are currently amended. Claims 1-4, 8-16, 18-21, 39-41 and 46-49 are examined on the merits within and are currently pending.
Modified Rejections
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 non-obviousness.
Claims 1-4, 8-16, 18-21, 39-41 and 46-49 are rejected under 35 U.S.C. 103 as being obvious over Bancel et al. (WO 2013/151666 A2) in view of Fry et al. (Fry et al., The many faces of IL-7. From Lymphopoiesis to Peripheral T Cell Maintenance. J Immunol, 2005 Jun 1;174(11):6571-6) and further in view of Galluzzo et al., (Galluzzo et al., Immunomodulating role of bisphosphonates on human gamma delta T cells: an intriguing and promising aspect of their antitumor activity. Expert Opinion on Therapeutic Targets, 11:7, 941-954, 2007) and Monteiro et al., (Monteiro et al., Liposomes in tissue engineering and regenerative medicine. J. R. Soc. Interface 11: 20140459).
Claims 1 and 49, Bancel et al. teach formulation of polynucleotides, primary modified mRNA (mmRNA), (0013), by lipid nanoparticles (000544) comprising cationic lipid (000563, at low pH or 000643 at neutral pH like DOTAP, DOTMA). The polynucleotide can conjugate to (000671) bisphosphonate as one of targeting groups. (000675). The polynucleotides or mmRNA may encode one or more biologics like cytokines. (000156). Interleukin-21 (IL21) modified mRNA (mRNA sequence shown in SEQ ID NO: 21686 (0001819) is the mRNA encoding IL21. Interleukin 7 (IL 7) modified mRNA (mRNA sequence shown in SEQ ID NO: 1656 (0001827) is the mRNA encoding IL7. (pg. 110 and 111, Table 5, Signal Squences). Example 174. Protein Expression Confirmation: Modified mRNA confirms the expression of protein IL21. (Table 215, pg. 714). Example 178. In Vitro Transfection of Interleukin 7: Interleukin (IL7) modified mRNA. (0001827).
Bancel et al. do not teach IL-7 is involved in regulating lymphoid homeostasis.
Fry et al. teach IL-7 is well known as a lymphopoietic cytokine, but recent studies have also identified a critical role for IL-7 in peripheral T cell homeostasis. IL-7 is well poised to serve as a homeostatic cytokine because it is produced by resting stromal cells, the IL-7R is present on most T cells, and IL-7 down-regulates its own receptor. These features allow IL-7 to signal large numbers of resting T cells and to be efficiently used when supplies are limiting. Consistent with this, in normal hosts, IL-7 is required for survival of naive T cell populations, and IL-7 contributes to homeostatic cycling of naive and memory cells. In addition, lymphopenic hosts accumulate increased levels of IL-7, and the supranormal levels are largely responsible for inducing homeostatic peripheral expansion in response to lymphopenia. Thus, IL-7 plays critical and nonredundant roles in both T cell lymphopoiesis and in maintaining and restoring peripheral T cell homeostasis. (Abs).
Bancel et al. teach the polynucleotide can conjugate to (000671) bisphosphonate in a lipid particle.
Fry et al. do not teach bisphosphonate in a lipid particle.
Moneiro et al. teach liposomes in tissue engineering and regenerative medicine. (Title). Bisphosphonate-coated liposomes displayed a strong binding to a collagen/hydroxyapatite (HA) composite scaffold, increasing their retention in the collagen/HA scaffolds after their subcutaneous implantation in rats [122]. The bisphosphonate coated liposomes were able to entrap BMP-2 and deliver it locally. (pg. 13, right col., last par.).
Galluzzo et al. teach nitrogen-containing bisphosphonates (N-BPs) play a crucial role in Vγ9Vδ2 T lymphocyte activation and in the acquisition of effector functions. TN-BPs influence the immune system in various but inter related ways, being able to enhance the innate and to promote the adaptive immune responses. (Abs).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare the lipid particle comprising cationic lipid, bisphosphonate conjugated to polynucleotide, and RNA encoding cytokine, like IL-17 taught by Bancel et al., to have cytokine involvement in regulating lymphoid homeostasis., since it is one of inherent properties of IL-17, taught by Fry et al., to have lipid particle coated bisphosphonate taught by Moneiro et al. and to know TN-BPs influence the immune system in various but inter related ways, taught by Galluzzo et al., since they have proven lipid particles comprising the above components are effective to deliver it locally and to promote the adaptive immune responses.
With regard to claim 2, Bancel et al. teach Table 3, a listing of 3’-untranslated region (UTRs) which may be utilized in the primary construct of the present invention as flanking regions. (000251), 3’UTR Identifier, 3UTR-011, Nnt1. Cardiotropin-like cytokine factor 1, sequence nucleotide encoding cytokine. (pg. 63). The polynucleotide, wherein said targeting moiety is a bisphosphonate. (Claim 37, pg. 758).
With regard to claims 3 and 4, Bancel et al. teach the polynucleotide, primary construct, and mmRNA can be formulated using one or more liposomes, lipoplexes, or lipid nanoparticles. Liposomes can be of different sizes such as, but not limited to, a multilamellar vesicle (MLV), which may contain a series of concentric bilayers. (000559). It would be obvious that multilamellae mean more than 2, and it can be 3 or more of lamellae per row.
With regard to claim 8, Bancel et al. teach bisphosphonate molecular weight, 283.11g/mol, or its molecular mass in the conjugate is 283.11 Da. (Bisphosphonate, 59 https://pubchem.ncbi.nlm.nih.gov/compound/25023903).
With regard to claims 13-16, Bancel et al. teach the polynucleotides, primary constructs and/or mmRNA may be formulated in a lipid-polycation complex which may further include a neutral lipid such as, but not limited to, cholesterol or dioleoyl phosphatidylethanolamine (DOPE), (000566), which can be called helper. The pharmaceutical compositions may be formulated in liposomes with neutral DOPC (l,2-dioleoyl-snglycero-3-phosphocholine). (000577). The cationic carrier may include, but is not limited to 1,2-Dioleoyl-3- Trimethylammonium-Propane (DOTAP), N-[1-(2,3 dioleoyloxy) propyl]-N,N,Ntrimethylammonium chloride (DOTMA). (000643).
With regard to claim 18, Bancel et al. teach liposomes can be of different sizes such as, but not limited to, a multilamellar vesicle (ML V) which may be hundreds of nanometers in diameter and may contain a series of concentric bilayers separated by narrow aqueous compartments, a small unicellular vesicle (SUV) which may be smaller than 50 nm in diameter, and a large unilamellar vesicle (LUV) which may be between 50 and 500 nm in diameter. (000559).
With regard to claim 19, Bancel et al. teach formulation of polynucleotides, primary modified mRNA (mmRNA), (0006), by lipid nanoparticles (000544) comprising cationic lipid (000563). The polynucleotide can conjugate to (000673) bisphosphonate as one of targeting groups. (000675). The polynucleotides or mmRNA may encode one or more biologics like cytokines. (000156).
The lipid vesicles are dispersed with the effective concentration of the entrapped substance for the production of liposomal products. (000560).
With regard to claim 20
Monteiro et al., teach lipid particle preparation by ethanol inject method, in which lipids dissolved in ethanol are rapidly injected into a buffer solution. (pg. 8, right col., 2nd par.). Bisphosphonate is soluble in the aqueous phase and can be added in the buffer solution. Hydrophilic bioactive agent, (like bisphosphonate) can be dissolved in the external aqueous phase, during liposome preparation, and become entrapped within the inner compartment of the liposome after solvent evaporation. (pg. 10, right col., last par.).
With regard to claim 21, Bancel et al. teach formulation of polynucleotides, primary modified mRNA (mmRNA), described in claim 1. In addition to traditional excipients such as any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, excipients can be included. (000544).
With regard to claims 39-41 and 47-48, “A method” is in the preamble and does not give patentable weight to the invention and not in the body of the claim. The pharmaceutical composition is described in claims 1, 21. Compositions are administered to humans, human patients or subjects. (000539).
Claim 39, Bancel et al. teach The synthetic nanocarriers may contain an immunostimulatory agent to enhance the immune response from delivery of the synthetic nanocarrier. (000613).
Claim 40, Bancel et al. teach The modified mRNA encoding G-CSF are transfected into the highly transfectable cell allowing for the production and secretion of G-CSF protein into the extracellular environment where G-CSF acts in a paracrine-like manner to stimulate the white blood cell expressing the G-CSF receptor to proliferate. (Example 40, pg. 505).
Claim 41, Bancel et al. teach mRNA as a therapeutic have been focused on applications that could immunization with mRNAs coding for cancer antigens. (0007), which is for preventing cancer.
In one embodiment, the synthetic nanocarrier may be formulated for use as a vaccine. In one embodiment, the synthetic nanocarrier may encapsulate at least one polynucleotide, primary construct and/or mmRNA which encode at least one antigen. As a non-limiting example, the synthetic nanocarrier may include at least one antigen and an excipient for a vaccine dosage form. (000616).
With regard to claims 47-48, “A method” is in the preamble and does not give patentable weight to the invention and not in the body of the claim.
Bancel et al. teach In certain embodiments, provided herein are combination therapeutics containing one or more polynucleotide, primary construct or mmRNA containing translatable regions that encode for a protein or proteins that boost a mammalian subject's immunity along with a protein that induces antibody-dependent cellular toxicity. For example, provided herein are therapeutics containing one or more nucleic acids that encode trastuzumab and granulocyte-colony stimulating factor (G-CSF). In particular, such combination therapeutics are useful in Her2+ breast cancer patients who develop induced resistance to trastuzumab. (000804).
With regard to claims 9-11 and 46
Bancel et al. do not teach bisphosphonate is a nitrogen-containing bisphosphonate, useful in immunotherapy and stimulates gamma delta T cells.
Galluzzo et al. teach nitrogen-containing bisphosphonates (N-BPs) play a crucial role in Vγ9Vδ2 T lymphocyte activation and in the acquisition of effector functions. TN-BPs influence the immune system in various but inter related ways, being able to enhance the innate and to promote the adaptive immune responses. For all these reasons, Vγ9Vδ2 T lymphocytes represent a particularly interesting target for immunotherapeutic protocols based on N-BP administration. Effects of N-BPs on the immune system have opened new and intriguing possibilities of therapeutic use for these drugs. (Abs).
With regard to claim 12,
Galluzzo et al. teach the more potent N-BPs have bulkier side chains characterized by a nitrogen moiety either in an alkyl chain e.g., alendronate and ibandronate or within a heterocyclic structure e.g., risedronate and zoledronic acid (ZA). (Pg. 942, left col., 1st par.).
With regard to claim 46,
Galluzzo et al. teach Nitrogen-containing bisphosphonates (N-BPs) play a crucial role in Vγ9Vδ2 T lymphocyte activation and in the acquisition of effector functions. The antitumor effect of bisphosphonates is exerted through direct as well as indirect mechanisms. An additional and not yet well explored mechanism by which N-BPs may display antineoplastic effect is related to their immunomodulatory properties. I N-BPs influence the immune system in various but inter related ways, being able to enhance the innate and to promote the adaptive immune responses. Vγ9Vδ2 T lymphocytes represent a particularly interesting target for immunotherapeutic protocols based on N-BP administration. (Abs).
Response to Arguments
With Regard to 35 U.S.C. § 103 Rejection:
Applicant argues that No reasonable expectation of success to arrive at the claimed invention.
This argument has been fully considered, but is not found persuasive, because “a reference is presumed operable until applicant provides facts rebutting the presumption of operability”. (MPEP 2121.02(I)). When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). See also MPEP § 716.07. See also In re Antor Media Corp., 689 F.3d 1282, 103 USPQ2d 1555 (Fed. Cir. 2012). Bancel et al. teach formulation of polynucleotides, primary modified mRNA (mmRNA), (0013), by lipid nanoparticles (000544) comprising cationic lipid (000563). The polynucleotide can conjugate to (000671) bisphosphonate as one of targeting groups. (000675). While the negatively charged bisphosphonates and the negatively charged RNA phosphate backbone theoretically compete for the positive charges of ionizable lipids during formulation, this competition can be managed through optimized formulation techniques. One with skill in the art, is known for solving the same problem, is represented with design choices, may modify the teachings of the prior arts until they can achieve better outcome results. LNPs used for RNA delivery are not simply lamellar liposomes; they are generally dense, core-shell nanoparticles with an ordered, non-lamellar internal organization designed to trap the RNA. It is reasonable to expect that a lipid nanoparticle (LNP) can be co-formulated with both RNA and a water-soluble bisphosphonate (BP) to deliver the RNA.
Applicant argues that There is no rationale or motivation to combine Bance[ and Galluzzo.
This argument has been fully considered, but is not found persuasive, because obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Bancel et al. teach the polynucleotide can conjugate to (000671) bisphosphonate in a lipid particle. Galluzzo et al. teach nitrogen-containing bisphosphonates (N-BPs) play a crucial role in Vγ9Vδ2 T lymphocyte activation and in the acquisition of effector functions. TN-BPs influence the immune system in various but inter related ways, being able to enhance the innate and to promote the adaptive immune responses. (Abs).
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 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 extension fee 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 date of this final action.
Correspondence
No claim is allowed.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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