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 .
Claims 1, 6-7, 10, 12-14, 18-19, 22-24, 27, 37, and 40 are pending.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01 June 2026 has been entered.
Status of the Application
Applicant’s response and amendment filed 01 June 2026 are acknowledged and entered.
Applicant has amended Claims 1, 10, 12-14, 19, and 22-24. Applicant has added Claim 40.
Response to Amendment
Applicant has amended Claim 19 to overcome the 112(a) written description (WD) rejections; the 112(a) WD rejection is withdrawn.
Applicant has amended Claim 24 to overcome the 112(b) rejections; the 112(b) rejections are withdrawn.
Applicant has amended Claim 23 to overcome the 112(d) rejections; the 112(d) rejections are withdrawn.
Applicant has amended Claims 1, 7, 10, 12-14, 18-19, 22-24, and 27 to overcome the 103 rejections; the 103 rejections are maintained and updated in response to the claim amendments.
The NSDP rejections are maintained and updated in response to the claim amendments.
Claims 1, 6-7, 10, 12-14, 18-19, 22-24, 27, 37, and 40 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Claim Interpretation
Claim 1 recites that the first formulation comprises a plurality of first NLPs that encapsulate a helper mRNA… as the only LNPs in the first formulation and the second formulation comprises a plurality of second LNPs that encapsulate a non-helper mRNA as the only LNPs in the second formulation.
The claim requires no specific LNP composition in either case (i.e., the LNPs don’t have to comprise any set amount of different lipids). Therefore, the recitation as the only LNPs in the first formulation is interpreted as meaning all the LNPs in the first formulation encapsulate an mRNA encoding hyaluronidase but the formulation itself can comprise any plurality of individual LNPs, each having its own lipid composition. Similarly, the recitation as the only LNPs in the second formulation is interpreted as meaning all the LNPs in the second formulation encapsulate any non-helper mRNA but the formulation itself can comprise any plurality of individual LNPs, each having its own lipid composition.
Claims 1 and 40 recite the hyaluronidase encoded by the helper mRNA…to the subject’s circulatory system…the second lipid nanoparticles are… enzymatic action of the hyaluronidase. Those are interpreted as inevitable outcomes of injecting to subcutaneous tissue of a subject the first and second formulations.
Claim Objections
Claim 19 is objected to because of the following informalities:
Claim 19 recites …prefilled for a single subcutaneous administration prior to injection. The bold/underlined part is redundant and should be deleted. Alternatively, the claim could be reworded: …wherein prior to injection, each first syringe and second syringe are prefilled for a single subcutaneous administration.
Appropriate correction is required.
REJECTIONS UPDATED IN RESPONSE TO AMENDMENT
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1, 6, 10, 12-13, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Pardi (et al. 2015. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Control. Releas. 217[10]:345-351, “Pardi”, of record), Frost (2007. Recombinant human hyaluronidase (rHuPH20): an enabling platform for subcutaneous drug and fluid administration. Expert Opin. Drug Deliv. 4[4]:427-440, “Frost”, of record on IDS), Turner (and Balu-Iyer. 11 Jan 2018. Challenges and Opportunities for the Subcutaneous Delivery of Therapeutic Proteins. J. Pharmaceut. Sci 107:1247-1260, “Turner”, of record), Kuhn (et al. 2012. mRNA as a Versatile Tool for Exogenous Protein Expression. Curr. Gene Ther. 12:347-361, “Kuhn”, of record), and Weissman (2014. mRNA transcript therapy. Expert Rev. Vaccin. 14[2]:265-281, “Weissman”, of record).
All references are of record.
This rejection has been updated in response to the claim amendments.
Pardi, drawn to expression kinetics of nucleoside-modified mRNA delivered in LNP to mice by various routes, teaches (§Abstract, §3.Results-3.2. mRNA-LNP administration into mice, entire §) subcutaneous (SC) injection of 5.0 µg of LNP-encapsulated mRNA resulted in protein production that occurred only at the site of injection. Meanwhile, Pardi teaches (§Abstract) intravenous [IV] and intraperitoneal [IP] and to a lesser extent intramuscular [IM] and intratracheal [IT] deliveries led to trafficking of mRNA-LNPs systemically resulting in active translation of the mRNA in the liver. Since Pardi delivered 5.0 µg of LNP-encapsulated mRNA, they delivered a plurality of LNPs.
That indicates that while some forms of administration (i.e., IV, IP, IM, and IT) result in more systemic delivery, SC administration results in protein production that is only local to the site of injection.
Pardi teaches (§4. Discussion ¶5) strength of protein production is influenced by the following factors:
1) the number of cells that are able to take up the mRNA-LNPs in the given tissue,
2) the amount of mRNA-LNPs that are taken up by cells,
3) the translational capacity of a specific cell type, and
4) the duration of time that the mRNA LNP is capable of being taken up by cells and translated (stability).
That indicates that the number of cells that is contacted by LNPs directly affects strength of protein production.
Pardi teaches (§5. Conclusion) mRNA is a promising non-viral delivery platform that has a bright future as a potent therapeutic and that delivery by LNPs that have performed well in clinical trials offers a clear step towards research application and clinical development.
That indicates that mRNA as a clinical drug delivery platform was of interest in the field.
Pardi teaches (§1. Introduction ¶3-4) efficient delivery of mRNA into target cells in vivo is a major challenge but formulations comprising LNPs protect the nucleic acid from nucleases and facilitate its uptake into cells.
Regarding Claims 10 and 12-13: Pardi teaches (§1. Introduction ¶3-4) the LNPs in their study comprise ionizable cationic lipids, phospholipid, cholesterol, and a PEGylated lipid. Pardi teaches (same §) LNPs containing ionizable cationic lipids represent one of the most advanced technological platforms. Pardi teaches (§2. Material and methods-2.4. Formulation of the mRNA ¶2) their LNPs contain an ionizable cationic lipid/phosphatidylcholine/cholesterol/PEG-lipid in the following ratio: 50 : 10 : 38.5 : 1.5 mol/mol. That indicates that their LNPs comprise a cationic lipid (Claim 10), PEG-lipid (Claim 12), and at least 1% of the total lipid is the PEG-lipid (i.e., 1.5% on a mol/mol basis) (Claim 13).
Note that (§2.6 Administration of LNPs to mice) Pardi’s mRNA-encapsulating LNPs are the only LNPs in their mRNA delivery formulation.
Pardi teaches SC administration but doesn’t teach anything about hyaluronidase.
Frost teaches (§Abstract) the extracellular matrix [ECM] is a significant barrier to the effective SC delivery of many drugs, limiting both pharmacokinetic parameters and injection volumes. Frost teaches (same §) the ECM limits the volume of drug that can be injected at a single site, and the rate and amount that reach the vascular compartment. Frost teaches (§1.2 Strategies to overcome the limitations of the extracellular matrix ¶1-4) SC drug administration presents many benefits to patients but:
unlike furred animals such as rodents that have loosely draped skin that can accommodate large volumes of subcutaneous fluid under the fascia without significant tissue distortion, humans and other furless animals have fibrous bands in the panniculus adiposus that reach into the deep fascia. These anchors reduce the compliance of the tissue space to injected fluids, such that subcutaneous liquids are generally limited to less than 2 mL.
Frost indicates that humans cannot accommodate large volumes of subcutaneous liquids and, therefore, cannot take advantage of the accessibility benefits of SC drug administration.
Frost teaches (§1.1 The extracellular matrix as a physiological barrier to drug delivery, entire §) the ECM prevents drugs, especially large molecule biologics, from accessing the vascular compartment, requiring that drugs must be delivered via IV administration.
Frost teaches (§1.2 Strategies to overcome the limitations of the extracellular matrix, final ¶) transiently degrading… hyaluronan in the interstitium could permit the conversion of many drugs from intravenous to local administration. Frost teaches (same §) that hyaluronan is the most feasible target within the ECM for degradation because the body rapidly turns it over.
Regarding Claim 6: Frost teaches (§1.3 Hyaluronidases: from spreading factors to the human genome ¶3) mammalian hyaluronidase is endo-β-N-acetyl-hexosaminidase.
Frost teaches (§1.3 Hyaluronidases: from spreading factors to the human genome ¶2) bovine and (§2. The development of rHuPH20, an rDNA-derived human hyaluronidase enzyme, entire § and §3. Development of Hylenex, recombinant [hyaluronidase human injection], entire §) recombinant human hyaluronidases are acceptable pharmaceutical products. Frost teaches (§5. Expert opinion, entire §) subcutaneous administration of drugs eliminates the loss of bioavailability, which may allow for lower and less frequent doses of drug. Frost teaches (same §) using hyaluronidase to increase the speed of absorption by SC injection has significant utility and can increase the surface area of local capillaries exposed to a drug and thereby increase the rate by which a drug is absorbed.
Frost teaches (§2.2 Development of a manufacturing process for rHuPH20, entire §) manufacturing recombinant hyaluronidase is a complicated process that requires expressing cDNA in Chinese Hamster Ovary cells followed by a four-step purification process OR expression followed by a 2-week fermentation cycle and subsequent purification. Either of those processes is time and resource intensive.
Frost teaches (§3. Development of Hylenex, recombinant [hyaluronidase human injection] ¶1, same §-3.1.1 Hypodermoclysis and same §-3.1.4 Absorption of radiopaque agents) SC injection of hyaluronidase followed by another treatment.
Altogether, Frost teaches that subcutaneous drug administration has many benefits, and that pretreating an area with hyaluronidase degrades the ECM which increases the circulatory system’s uptake of a drug (i.e., since the ECM is degraded, there is increased capillary surface area that is exposed to a drug). Frost also teaches that pretreatment with hyaluronidase is necessary when subcutaneously administering a drug to a human furless animals don’t accommodate more than 2 mL of subcutaneous fluids. Frost indicates that synthesizing recombinant hyaluronidase is a time-consuming and resource-intensive process.
Frost’s teachings indicate that it was well established in the pharmaceutical arts to administer HYAL to degrade the ECM and improve uptake of a fluid or fluid drug by a subject’s circulatory system.
Pardi and Frost do not teach administering a LNP encapsulating a hyaluronidase-encoding mRNA before administering a LNP encapsulating an mRNA drug.
However, Turner, drawn to subcutaneous delivery of protein therapeutics, teaches (§Immune response to therapeutic proteins ¶1) antidrug antibodies (ADAs) may impact the pharmacokinetics of these [i.e., protein] therapeutics by altering clearance but also effect the safety and efficacy by severely or completely diminishing pharmacological activity. Turner teaches (§Formulation Excipients and Additives¶1-2) HYAL has benefits in drug delivery but unfortunately, case studies have shown a risk of immunogenicity against hyaluronidase. Turner also teaches (§Abstract) subcutaneous administration of biologics is convenient and lowers costs because it can be performed at home.
Kuhn teaches (§Abstract, §Introduction ¶2) there are advantages of administering mRNA for protein expression, including in clinical applications. Kuhn teaches (§PRECLINICAL AND CLINICAL APPLICATIONS OF RNA-Induction of Antigen-Specific Immune Responses ¶6) administering mRNA to induce protein expression is advantageous because it has a low cost and long storage time. Kuhn teaches (§mRNA-Based Gene Therapy, entire §) RNA transfection performs well in the clinic, and conveys advantages, namely that modified nt within the mRNA decrease binding to a body’s pattern recognition receptors, and mRNA can be administered without inducing interferon response.
Additionally, Weissman teaches the benefits of mRNA transcript therapy. Weissman is drawn to a review of using mRNA in therapy including protein replacement therapy. Weissman teaches (§Introduction ¶2) using mRNA has advantages compared to other nucleic acid-based approaches, specifically that mRNA does not have the risk of integration into the chromosomes which can lead to insertional mutagenesis, and that mRNA results in only transient translation which can be beneficial for some applications. Weissman teaches in principle, mRNA-based therapies appear to be much safer than DNA or viral and are applicable to a broad spectrum of disorders both acute and chronic. Weissman teaches (§Protein replacement therapies ¶1) mRNA-based therapeutics deliver a natural product whose components are all found in an organism and that it allows robust and tunable delivery of the encoded protein.
Weissman teaches that mRNA-based therapeutics can be more cost-effective than administering protein because using mRNA avoids the expensive manufacturing of therapeutic proteins in fermentation tanks and protein-specific purification procedures. All of these attributes allow mRNA the potential to reduce cost and time for entry into clinical testing... Weissman teaches (same § ¶2) that delivering therapeutic proteins by delivering mRNA is obvious:
delivery of therapeutic proteins by mRNA is an obvious therapeutic objective. The delivery of such encoded proteins can be initially divided between extracellular acting and systemic proteins versus intracellular acting proteins and then further divided based on; short-term delivery to treat deficient or non-functional proteins…and acute site-specific or systemic delivery of a protein during a medical emergency or therapeutic procedure.
Other parts of the review discuss other considerations such as clinical development of therapeutic mRNA.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify Pardi’s subcutaneous method of mRNA administration (wherein protein production was limited to the site of injection) with Frost’s teachings about teachings about hyaluronidase degrading the ECM to improve circulatory uptake of fluids and fluid drugs, Turner’s teachings about advantages of subcutaneous delivery and detriments of immune response to protein therapeutics, Kuhn’s teachings about benefits—including immunological benefits—of mRNA therapies, and Weissman’s teachings about the cost benefits of mRNA therapy vs protein therapy. It would have been obvious to deliver the HYAL enzyme as an mRNA because Turner teaches downsides of administering HYAL protein but Kuhn and Weissman teach immunological and cost-savings benefits of delivering mRNA to induce protein expression rather than delivering protein itself. It would have been obvious to deliver mRNA encoding mammalian hyaluronidase endo-β-N-acetyl-hexosaminidase when administering the method to a mammal.
One would have done so for the benefit of improving circulatory uptake of mRNAs by breaking down the ECM, thereby turning SC delivery from a local site-only delivery method to a systemic delivery method, and for the benefit of producing an easy, low cost method of administering an mRNA therapeutic subcutaneously. It would have been obvious to administer LNP-encapsulated HYAL-encoding mRNA because LNP-encapsulated mRNA was known to be good for in vivo delivery (i.e., Pardi), because Frost teaches that hyaluronidase degrades the ECM and improves circulatory uptake of drugs, because the teachings of Kuhn and Turner indicate that administering mRNA has a preferable immunological profile to administering protein, and because of Weissman’s teachings about mRNA having lower cost vs. protein therapy.
One would have been motivated to do so with a reasonable expectation of success because LNP-encapsulated mRNA was known (i.e., Pardi), because HYAL was known to degrade the ECM thereby improving drug uptake by the circulatory system (Frost), because protein therapeutics including HYAL are immunogenic (Turner), but Kuhn teaches administering mRNA therapeutics avoids immune system stimulation. One would have been motivated because Weissman taught that delivering mRNA is advantageous over delivering protein because (§Clinical development of therapeutic mRNA ¶5) manufacturing mRNA is easy and has fewer risks than producing recombinant protein:
manufacturing of mRNA under current day techniques is relatively simple. Therapeutic mRNA can be made in a single reaction using template DNA and phage polymerase with NTPs and buffer. There are no animal or cellular components; thus, the risks are considerably lower compared to recombinant proteins.
An artisan would have readily understood from the teachings of Pardi, Frost, Turner, Kuhn, and Weissman that using a HYAL-encoding mRNA to degrade a subject’s ECM and thereby increase absorption of LNPs comprising any drug, including mRNA, by the subject’s capillaries would cost-effectively improve uptake of any subsequently administered subcutaneously-delivered drug (including mRNA).
An artisan would have done so because of Pardi’s teaching that (§4. Discussion ¶5) strength of protein production is influenced by the number of cells that take up mRNA-LNPs and Frost’s teaching that (§5.2 Modified pharmacokinetics following subcutaneous injection with rHuPH20) degrading the ECM increases the surface area of capillaries exposed to an injected drug which increases the rate by which compounds are absorbed.
It would have been obvious to encapsulate the HYAL-encoding mRNA in a LNP, a LNP comprising a cationic, or a LNP comprising at least 1% PEG-modified lipid because Pardi shows successfully using such LNP in vivo and teaches (§1. Introduction ¶4, §4. Discussion ¶2) such LNP are one of the most advanced technological platforms for in vivo delivery.
Therefore, Pardi, Frost, Turner, Kuhn, and Weismann make obvious a method for subcutaneous delivery, the method comprising: (1) subcutaneously injecting to a subject a first formulation comprising LNPs encapsulating a hyaluronidase-encoding mRNA and (2) then subcutaneously injecting to the same tissue of the subject a separate, second formulation comprising LNPs encapsulating a second, therapeutic mRNA drug. The hyaluronidase encoded by the mRNA would have been expressed within the subcutaneous tissue and would have enzymatically degraded the ECM, which would have increased exposure to the subject’s circulatory system in preparation for the second, therapeutic mRNA drug. Then, the second formulation comprising LNPs encapsulating the therapeutic mRNA drug would have entered the circulatory system due to the degradation of the ECM by the hyaluronidase.
Therefore, all the limitations of Claims 1, 6, 10, 12-13, and 40 would have been obvious in view of Pardi, Frost, Turner, Kuhn, and Weismann.
Claims 1, 6, 10, 12-14, 22-23, 37, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Pardi, Frost, Turner, Kuhn, and Weismann as applied to claims 1, 6, 10, 12-13, and 40 above, and further in view of International Publication Number WO917 (published 22 October 2009, of record).
All references are of record.
This rejection has been updated in response to the claim amendments.
NOTE: page # references in WO documents refer to the PDF page #.
The teachings of Pardi, Frost, Turner, Kuhn, and Weismann as applicable to Claim(s) 1, 6, 10, 12-13, and 40 have been described in the 103 rejection above.
Pardi, Frost, Turner, Kuhn, and Weismann teach a method for subcutaneous mRNA delivery to a subject comprising injecting into a subject’s subcutaneous tissue a first formulation comprising a plurality of LNPs that encapsulate a hyaluronidase-encoding mRNA (which would result in the hyaluronidase encoded by the mRNA being expressed and degrading the ECM, thereby increasing exposure to the subject’s circulatory system) and then injecting to the same subcutaneous tissue a separate, second formulation of a plurality of LNPs encapsulating a therapeutic (or other, nonhyaluronidase-encoding) mRNA (wherein the second LNPs would enter the subject’s circulatory system due to the hyaluronidase’s degradation of the ECM).
Pardi, Frost, Turner, Kuhn, and Weismann do not explicitly teach the HYAL-encoding mRNA and the therapeutic mRNA are administered in separate formulations (Claim 1). Pardi, Frost, Turner, Kuhn, and Weismann do not teach that the LNP is a liposome (Claim 14), the first and second LNPs comprise different lipids to form non-identical compositions (Claim 22), or the HYAL-encoding mRNA is injected within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours prior to administering the first mRNA composition (Claim 23).
However, WO917 teaches the limitations that the other references do not teach. WO917 is drawn to compositions comprising a hyaluronan (HA)-degrading enzyme (such as hyaluronidase, HYAL) for treating HA-associated conditions/diseases/disorder. WO917 teaches (pp. 2-3 L30-5) administering a HA-degrading enzyme alone or in combination with other treatments.
Regarding Claim 1 and administering separate formulations: WO917 teaches (p. 2 L24-31) administering a HYAL composition in combination with another treatment. WO917 teaches (p. 3 L13-16) HA-degrading enzymes have been used therapeutically, typically as dispersing and spreading agents in combination with other therapeutic agents. WO917 teaches (p. 6 L10-16) administering a second agent for treating a disease or condition. WO917 teaches (p. 7 L10-15) the second agent can be a nucleic acid. WO917 teaches (p. 6 L14-16) the second agent and the composition containing the HYAL are administered separately, such as simultaneously, sequentially or intermittently in any order. Administration in separate formulations is a limitation of instant Claim 1.
Regarding Claim 14: WO917 teaches (pp. 118-119 L10-25) using liposomes to administer compositions.
Regarding Claim 22: WO917 teaches (p. 119 L9-25) liposomes interact with cells via different mechanisms and varying the liposome formulation can alter which mechanism is operative although more than one mechanism can operate at the same time. WO917 teaches the following mechanisms:
endocytosis by phagocytic cells of the reticuloendothelial system such as macrophages and neutrophils; adsorption to the cell surface, either by nonspecific weak hydrophobic or electrostatic forces, or by specific interactions with cell-surface components; fusion with the plasma cell membrane by insertion of the lipid bilayer of the liposome into the plasma membrane, with simultaneous release of liposomal contents into the cytoplasm; and by transfer of liposomal lipids to cellular or subcellular membranes, or vice versa, without any association of the liposome contents.
Regarding Claim 23: WO917 teaches (p. 6 L24-31) the second agent is administered at various time points after the HYAL is administered:
the second agent is administered at least 0.5 minutes, at least one minute, at least five minutes, at least fifteen minutes, at least thirty minutes, at least one hour or more than one hour after the composition containing the soluble hyaluronidase is administered. In some examples, the second agent is administered at least or two hours, four hours, six hours, eight hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after the composition containing the soluble hyaluronidase is administered.
Administering the HYAL 30 min (i.e. “0.5 hours”), 15 min (=0.25 hours), at least 5 min (which includes at least 6 min, which = 0.1 hours), or 1 hour before administering the second agent are simply different terms used to describe administering the “first formulation encapsulating a helper mRNA encoding a HYAL” (i.e., HYAL-encoding mRNA) prior or 1 hour prior to injecting the “second formulation encapsulating a non-helper mRNA” (i.e., second mRNA encoding any protein). Therefore, WO917 teaches limitations of Claims 1, 14, and 22-23.
WO917 teaches (p.10 L1-10) the HYAL and/or second agent can be administered locally or systemically, such as…subcutaneously… [or] topically.
WO917 teaches (p. 155 §3. Use as a spreading agent and p. 158 §6. Gene therapy applications) benefits to administering HYAL before administering another drug including another gene therapy drug. Such benefits include that HYAL facilitates diffusion and delivery because the extracellular matrix (ECM) can hinder movement:
hyaluronidases can be used to facilitate the diffusion and, therefore, promote the delivery, of small molecule pharmacologic agents as well as larger molecule pharmacologic agents, such as proteins, nucleic acids and ribonucleic acids, and macromolecular compositions… [comprising] a combination of components including… nucleic acids… lipids, lipid-based molecules and drugs. For example, molecules and macromolecular complexes ranging from about 10 nm to about 500 nm in diameter, can exhibit dramatic improvements in delivery through interstitial spaces when the interstitial space has been previously, or is coincidently, exposed to hyaluronidase.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the methods for subcutaneous delivery of a helper mRNA encoding HYAL encapsulated in LNPs of Pardi, Frost, Turner, Kuhn, and Weismann with kinds of formulations and instructions for order/timeframe of injection of WO917 (including a first subcutaneous injection with LNPs encapsulating a hyaluronidase-encoding mRNA and a subsequent subcutaneous injection with LNPs encapsulating a therapeutic gene-encoding mRNA [i.e., “a non-helper mRNA”]) for the benefits of breaking down the ECM with mammalian HYAL to improve delivery of the LNPs containing a non-helper mRNA inside of a mammalian subject. One would have been motivated to do so with a reasonable expectation of success because Frost teaches using hyaluronidase to break down the ECM prior to administration of a drug, and because the timepoints taught by WO917 would have provided the benefit of allowing the HYAL mRNA to be translated and the HYAL protein to break down the ECM before administration of the second mRNA. Using a mammalian HYAL would have been of obvious benefit when delivering mRNA to a mammal because an artisan of ordinary skill would have known that enzymes are evolutionarily conserved and a mammalian HYAL would work effectively in a mammal and (WO917 p. 80 L5-16) be less immunogenic vs. a bacterial HYAL or HYAL from a leech.
It would have been obvious to use LNPs that are liposomes, including liposomes whose formulation vary (as taught by WO917) for the benefit of testing different lipid formulations to determine which lipid formulations produce cell entry by the most efficacious mechanism and the benefit of fine-tuning the delivery system depending on target cell or tissue type. One would have done so with a reasonable expectation of success because WO917 teaches liposomes interact with cells via different mechanisms and that varying liposome formulation can alter which mechanism(s) is operative.
Therefore, modifying the methods of Pardi, Frost, Turner, Kuhn, and Weismann with the teachings of WO917 would have produced all the limitations of Claims 1, 6, 10, 12-14, 22-23, and 40.
Claim(s) 1, 6-7, 10, 12-14, 22-23, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Pardi, Frost, Turner, Kuhn, Weismann, and WO917 as applied to claims 1, 6, 10, 12-14, 22-23, and 40 above, and further in view of WO2013/151774 (published on 10 October 2013, “WO774”, of record) and NCBI (1998. “Homo sapiens hyaluronidase (LUCA-3) mRNA, complete cds | GenBank: AF040710.1”. Available online at ncbi.nlm.nih.gov/. Accessed on 04 August 2025, “NCBI”, of record).
All references are of record.
This rejection has been updated in response to the claim amendments.
NOTE: page # references in WO documents refer to the PDF page #.
The teachings of Pardi, Frost, Turner, Kuhn, Weismann, and WO917 as applicable to Claim(s) 1, 6, 10, 12-13, and 40 have been described in the 103 rejection above.
Pardi, Frost, Turner, Kuhn, Weismann, and WO917 teach a method for subcutaneous mRNA delivery to a subject comprising injecting into a subject’s subcutaneous tissue a first formulation comprising a plurality of LNPs that encapsulate a hyaluronidase-encoding mRNA (which would result in the hyaluronidase encoded by the mRNA being expressed and degrading the ECM, thereby increasing exposure to the subject’s circulatory system) and then subsequently injecting to the same subcutaneous tissue a separate, second formulation of a plurality of LNPs encapsulating a therapeutic (or other, nonhyaluronidase-encoding, or “non-helper”) mRNA (wherein the second LNPs would enter the subject’s circulatory system due to the hyaluronidase’s degradation of the ECM).
WO917 teaches (p. 10 L25-30) the HYAL used in their methods can be a PH20, including bovine or human PH20.
Pardi, Frost, Turner, Kuhn, Weismann, and WO917 do not teach the HYAL mRNA comprises the polynt sequence of SEQ ID NOs 10 or 12 (Claim 7).
Regarding Claim 7: However, WO774, drawn to a combination therapy comprising an anti-HA agent and another therapeutic agent, teaches polynt sequences comprising SEQ ID NO 10. WO774 teaches (p. 3 L10-15) HYAL enzymes, including PH20. WO774 teaches (p. 25 L15-20) SEQ ID NO 190, which encodes a bovine HYAL. WO774’s SEQ ID NO 190 comprises 100% identity to claimed SEQ ID NO 10, as shown by the following alignment:
SEQ ID NO 10
ID BAV41285 standard; DNA; 2105 BP.
XX
AC BAV41285;
XX
DT 05-DEC-2013 (first entry)
XX
DE Bos taurus Hyaluronidase PH20 DNA, SEQ 190.
XX
KW Hyaluronidase PH20; breast tumor; cancer; chemotherapy; colon tumor;
KW cytostatic; ds; head and neck tumor; lung tumor; ovary tumor;
KW pancreas tumor; prostate tumor; protein therapy; solid tumor;
KW therapeutic; uterine cervix tumor.
XX
OS Bos taurus.
XX
CC PN WO2013151774-A1.
XX
CC PD 10-OCT-2013.
XX
CC PF 15-MAR-2013; 2013WO-US032684.
XX
PR 04-APR-2012; 2012US-0686429P.
PR 16-OCT-2012; 2012US-0714719P.
XX
CC PA (HALO-) HALOZYME INC.
XX
CC PI Maneval DC, Shepard HM, Thompson CB;
XX
DR WPI; 2013-Q86216/70.
XX
CC PT Combination useful for treating cancer e.g. solid tumor, pancreatic
CC PT cancer, ovarian cancer, lung cancer, colon cancer, prostate cancer
CC PT comprises composition containing anti-hyaluronan agent; and composition
CC PT containing tumor-targeted taxane.
XX
CC PS Disclosure; SEQ ID NO 190; 230pp; English.
XX
CC The present invention relates to a novel composition, useful for treating
CC cancer in an individual. The composition comprises a composition
CC containing anti-hyaluronan agent, and a composition containing tumor-
CC targeted taxane, where the anti-hyaluronic agent is hyaluronidase enzyme.
CC The hyaluronidase used can be bacterial hyaluronidase (EC 4.2.2.1 or EC
CC 4.2.99.1), hyaluronidase from leeches, other parasites and crustaceans
CC (EC 3.2.1.36) and mammalian-type hyaluronidase (EC 3.2.1.35). The
CC invention further discloses a method for treating a cancer by
CC administering the above combination composition. The composition is used
CC as a combination for treating a cancer e.g., tumor, solid tumor, tumor
CC having increased cellular and/or stromal expression of hyaluronan,
CC compared to a non-cancerous tissue of the same tissue type or compared to
CC a non-metastatic tumor of the same tumor-type, pancreatic cancer, ovarian
CC cancer, lung cancer, colon cancer, prostate cancer, cervical cancer, head
CC and neck cancer and breast cancer. The combination of anti-hyaluronan
CC agent and tumor-targeted taxane shows synergistic effect for treating
CC cancer i.e., the combination results in a significantly improved efficacy
CC on tumor growth inhibition compared to the individual treatments at the
CC same dose. The anti-hyaluronan agent degrades tumor-associated
CC hyaluronan, and tumor-targeted taxane achieves intratumoral delivery. The
CC tumor-targeted taxane formulation reduces intratumoral nucleoside
CC deaminase protein levels or protein activity compared to the levels or
CC activity of the nucleoside deaminase in the absence of the intratumoral
CC taxane formulation. The combination composition increases the
CC intratumoral activity of a nucleoside analog. The present sequence
CC represents a nucleotide encoding Bos taurus Hyaluronidase PH20, which may
CC be used in the generation of the novel composition of the invention.
XX
SQ Sequence 2105 BP; 723 A; 420 C; 407 G; 555 T; 0 U; 0 Other;
Query Match 100.0%; Score 1661; Length 2105;
Best Local Similarity 100.0%;
Matches 1661; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ATGAGAATGCTGAGGCGCCACCATATCTCCTTTCGGAGCTTTGCTGGGTCTAGCGGAACA 60 SEQ ID NO 10
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 295 ATGAGAATGCTGAGGCGCCACCATATCTCCTTTCGGAGCTTTGCTGGGTCTAGCGGAACA 354 WO774 SEQ ID NO 190
Qy 61 CCCCAGGCAGTGTTCACCTTCCTTCTGCTTCCGTGTTGTTTGGCTCTGGACTTCAGAGCA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 355 CCCCAGGCAGTGTTCACCTTCCTTCTGCTTCCGTGTTGTTTGGCTCTGGACTTCAGAGCA 414
Qy 121 CCCCCTCTTATTTCAAACACTTCTTTCCTCTGGGCCTGGAATGCCCCAGTTGAACGTTGT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 415 CCCCCTCTTATTTCAAACACTTCTTTCCTCTGGGCCTGGAATGCCCCAGTTGAACGTTGT 474
Qy 181 GTTAACAGAAGATTTCAACTACCTCCAGATCTGAGACTCTTCTCTGTAAAAGGAAGCCCC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 475 GTTAACAGAAGATTTCAACTACCTCCAGATCTGAGACTCTTCTCTGTAAAAGGAAGCCCC 534
Qy 241 CAGAAAAGTGCTACCGGACAATTTATTACATTATTTTATGCTGATAGACTTGGCTACTAT 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 535 CAGAAAAGTGCTACCGGACAATTTATTACATTATTTTATGCTGATAGACTTGGCTACTAT 594
Qy 301 CCTCATATAGATGAAAAAACAGGCAAAACCGTATTCGGAGGAATTCCCCAGTTGGGAAAC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 595 CCTCATATAGATGAAAAAACAGGCAAAACCGTATTCGGAGGAATTCCCCAGTTGGGAAAC 654
Qy 361 TTAAAAAGTCATATGGAGAAAGCAAAAAATGACATTGCCTATTACATACCAAATGACAGC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 655 TTAAAAAGTCATATGGAGAAAGCAAAAAATGACATTGCCTATTACATACCAAATGACAGC 714
Qy 421 GTGGGCTTGGCGGTCATTGACTGGGAAAACTGGAGGCCTACCTGGGCAAGAAACTGGAAA 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 715 GTGGGCTTGGCGGTCATTGACTGGGAAAACTGGAGGCCTACCTGGGCAAGAAACTGGAAA 774
Qy 481 CCTAAAGATGTTTACAGGGATGAGTCAGTTGAGTTGGTTCTGCAAAAAAATCCGCAACTC 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 775 CCTAAAGATGTTTACAGGGATGAGTCAGTTGAGTTGGTTCTGCAAAAAAATCCGCAACTC 834
Qy 541 AGTTTCCCAGAGGCTTCCAAGATTGCAAAAGTGGATTTTGAGACAGCAGGAAAGAGTTTC 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 835 AGTTTCCCAGAGGCTTCCAAGATTGCAAAAGTGGATTTTGAGACAGCAGGAAAGAGTTTC 894
Qy 601 ATGCAAGAGACTTTAAAACTGGGAAAATTACTTCGGCCAAATCACTTATGGGGTTATTAT 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 895 ATGCAAGAGACTTTAAAACTGGGAAAATTACTTCGGCCAAATCACTTATGGGGTTATTAT 954
Qy 661 CTTTTTCCTGATTGTTACAATCATAATCATAACCAACCTACTTACAATGGAAATTGCCCT 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 955 CTTTTTCCTGATTGTTACAATCATAATCATAACCAACCTACTTACAATGGAAATTGCCCT 1014
Qy 721 GATGTAGAAAAAAGGAGAAATGATGATCTCGAGTGGTTGTGGAAGGAAAGCACTGCCCTT 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1015 GATGTAGAAAAAAGGAGAAATGATGATCTCGAGTGGTTGTGGAAGGAAAGCACTGCCCTT 1074
Qy 781 TTCCCTTCTGTTTATTTGAATATCAGGTTAAAATCTACTCAAAATGCTGCCTTGTATGTT 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1075 TTCCCTTCTGTTTATTTGAATATCAGGTTAAAATCTACTCAAAATGCTGCCTTGTATGTT 1134
Qy 841 CGTAATCGTGTCCAGGAAGCCATTCGGTTGTCTAAAATAGCGAGTGTCGAAAGTCCACTT 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1135 CGTAATCGTGTCCAGGAAGCCATTCGGTTGTCTAAAATAGCGAGTGTCGAAAGTCCACTT 1194
Qy 901 CCGGTTTTTGTATATGCCCGTCCAGTTTTTACTGATGGGTCTTCAACATATCTTTCTCAG 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1195 CCGGTTTTTGTATATGCCCGTCCAGTTTTTACTGATGGGTCTTCAACATATCTTTCTCAG 1254
Qy 961 GGTGACCTTGTGAATTCGGTTGGTGAGATCGTTTCTCTAGGTGCCTCTGGGATTATAATG 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1255 GGTGACCTTGTGAATTCGGTTGGTGAGATCGTTTCTCTAGGTGCCTCTGGGATTATAATG 1314
Qy 1021 TGGGGCAGTCTCAATCTAAGCTTATCTATGCAATCTTGCATGAACCTAGGCACTTACTTG 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1315 TGGGGCAGTCTCAATCTAAGCTTATCTATGCAATCTTGCATGAACCTAGGCACTTACTTG 1374
Qy 1081 AACACTACACTGAATCCTTACATAATCAACGTCACCCTAGCCGCCAAAATGTGCAGCCAA 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1375 AACACTACACTGAATCCTTACATAATCAACGTCACCCTAGCCGCCAAAATGTGCAGCCAA 1434
Qy 1141 GTGCTTTGCCACAATGAAGGAGTGTGTACAAGGAAACACTGGAATTCAAGCGACTATCTT 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1435 GTGCTTTGCCACAATGAAGGAGTGTGTACAAGGAAACACTGGAATTCAAGCGACTATCTT 1494
Qy 1201 CACCTGAACCCAATGAATTTTGCTATTCAAACTGGGGAAGGTGGAAAATACACAGTACCT 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1495 CACCTGAACCCAATGAATTTTGCTATTCAAACTGGGGAAGGTGGAAAATACACAGTACCT 1554
Qy 1261 GGGACAGTCACACTTGAAGACTTGCAAAAGTTTTCTGATACATTTTATTGCAGTTGTTAT 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1555 GGGACAGTCACACTTGAAGACTTGCAAAAGTTTTCTGATACATTTTATTGCAGTTGTTAT 1614
Qy 1321 GCCAACATCCACTGTAAGAAGAGAGTTGATATAAAAAATGTTCATAGTGTTAACGTGTGT 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1615 GCCAACATCCACTGTAAGAAGAGAGTTGATATAAAAAATGTTCATAGTGTTAACGTGTGT 1674
Qy 1381 ATGGCAGAAGACATTTGTATAGACAGCCCTGTGAAGTTACAACCCAGTGATCATTCCTCC 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1675 ATGGCAGAAGACATTTGTATAGACAGCCCTGTGAAGTTACAACCCAGTGATCATTCCTCC 1734
Qy 1441 AGCCAGGAGGCATCTACTACCACCTTCAGCAGTATCTCACCCTCCACTACAACTGCCACA 1500
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1735 AGCCAGGAGGCATCTACTACCACCTTCAGCAGTATCTCACCCTCCACTACAACTGCCACA 1794
Qy 1501 GTATCTCCATGTACTCCTGAGAAACACTCCCCTGAGTGCCTCAAAGTCAGGTGTTCGGAA 1560
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1795 GTATCTCCATGTACTCCTGAGAAACACTCCCCTGAGTGCCTCAAAGTCAGGTGTTCGGAA 1854
Qy 1561 GTCATCCCCAACGTCACCCAAAAGGCGTGTCAAAGTGTTAAATTGAAGAACATTTCCTAT 1620
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1855 GTCATCCCCAACGTCACCCAAAAGGCGTGTCAAAGTGTTAAATTGAAGAACATTTCCTAT 1914
Qy 1621 CAGTCACCTATTCAAAATATTAAAAATCAAACAACCTATTA 1661
|||||||||||||||||||||||||||||||||||||||||
Db 1915 CAGTCACCTATTCAAAATATTAAAAATCAAACAACCTATTA 1955
In addition, the art of NCBI teaches that the human sequence of HYAL was known. NCBI teaches HYAL comprises 100% sequence identity to claimed SEQ ID NO 12, as shown by the following alignment:
RESULT 1
AF040710
LOCUS AF040710 1861 bp mRNA linear PRI 05-NOV-1998
DEFINITION Homo sapiens hyaluronidase (LUCA-3) mRNA, complete cds.
ACCESSION AF040710
VERSION AF040710.1
KEYWORDS .
SOURCE Homo sapiens (human)
ORGANISM Homo sapiens
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
REFERENCE 1 (bases 1 to 1861)
AUTHORS Fong,K., Bader,S., Lee,C.-C., Latif,F., Sekido,Y., Duh,F.-M.,
Wei,M.-H., Cundiff,S., Lerman,M.I. and Minna,J.D.
TITLE LUCA-3 a third hyaluronidase gene and candidate tumor suppressor
gene located in the 3p21.3 homozygous deletion region
JOURNAL Unpublished
REFERENCE 2 (bases 1 to 1861)
AUTHORS Minna,J.D. and Lerman,M.I.
TITLE Direct Submission
JOURNAL Submitted (02-JAN-1998) Hamon Center for Therapeutic Oncology
Research, University of Texas Southwestern Medical Center, 5323
Harry Hines Blvd., Dallas, TX 75235-8593, USA
FEATURES Location/Qualifiers
source 1..1861
/organism="Homo sapiens"
/mol_type="mRNA"
/db_xref="taxon:9606"
/chromosome="3"
/map="3p21.3"
/note="small cell lung cancer homozygous deletion region"
gene 1..1861
/gene="LUCA-3"
CDS 194..1585
/gene="LUCA-3"
/note="one of a family of three hyaluronidase genes
located at 3p21.3 and related in sequence to PH-20"
/codon_start=1
/product="hyaluronidase"
/protein_id="AAC70915.1"
/translation="MTTQLGPALVLGVALCLGCGQPLPQVPERPFSVLWNVPSAHCEA
RFGVHLPLNALGIIANRGQHFHGQNMTIFYKNQLGLYPYFGPRGTAHNGGIPQALPLD
RHLALAAYQIHHSLRPGFAGPAVLDWEEWCPLWAGNWGRRRAYQAASWAWAQQVFPDL
DPQEQLYKAYTGFEQAARALMEDTLRVAQALRPHGLWGFYHYPACGNGWHSMASNYTG
RCHAATLARNTQLHWLWAASSALFPSIYLPPRLPPAHHQAFVRHRLEEAFRVALVGHR
HPLPVLAYVRLTHRRSGRFLSQDDLVQSIGVSAALGAAGVVLWGDLSLSSSEEECWHL
HDYLVDTLGPYVINVTRAAMACSHQRCHGHGRCARRDPGQMEAFLHLWPDGSLGDWKS
FSCHCYWGWAGPTCQEPSLGLKKQYKARAPATASSFPCCHFSSPGTTLSHSCSIQFTV
NPPKHTPRFPWNP
Query Match 100.0%; Score 1392; Length 1861;
Best Local Similarity 100.0%;
Matches 1392; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ATGACCACGCAACTGGGCCCAGCCCTGGTGCTGGGGGTGGCCCTGTGCCTGGGTTGTGGC 60 SEQ ID NO 12
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 194 ATGACCACGCAACTGGGCCCAGCCCTGGTGCTGGGGGTGGCCCTGTGCCTGGGTTGTGGC 253 HYAL mRNA
Qy 61 CAGCCCCTACCACAGGTCCCTGAACGCCCCTTCTCTGTGCTGTGGAATGTACCCTCAGCA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 254 CAGCCCCTACCACAGGTCCCTGAACGCCCCTTCTCTGTGCTGTGGAATGTACCCTCAGCA 313
Qy 121 CACTGTGAGGCCCGCTTTGGTGTGCACCTGCCACTCAATGCTCTGGGCATCATAGCCAAC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 314 CACTGTGAGGCCCGCTTTGGTGTGCACCTGCCACTCAATGCTCTGGGCATCATAGCCAAC 373
Qy 181 CGTGGCCAGCATTTTCACGGTCAGAACATGACCATTTTCTACAAGAACCAACTCGGCCTC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 374 CGTGGCCAGCATTTTCACGGTCAGAACATGACCATTTTCTACAAGAACCAACTCGGCCTC 433
Qy 241 TATCCCTACTTTGGACCCAGGGGCACAGCTCACAATGGGGGCATCCCCCAGGCTTTGCCC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 434 TATCCCTACTTTGGACCCAGGGGCACAGCTCACAATGGGGGCATCCCCCAGGCTTTGCCC 493
Qy 301 CTTGACCGCCACCTGGCACTGGCTGCCTACCAGATCCACCACAGCCTGAGACCTGGCTTT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 494 CTTGACCGCCACCTGGCACTGGCTGCCTACCAGATCCACCACAGCCTGAGACCTGGCTTT 553
Qy 361 GCTGGCCCAGCAGTGCTGGATTGGGAGGAGTGGTGTCCACTCTGGGCTGGGAACTGGGGC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 554 GCTGGCCCAGCAGTGCTGGATTGGGAGGAGTGGTGTCCACTCTGGGCTGGGAACTGGGGC 613
Qy 421 CGCCGCCGAGCTTATCAGGCAGCCTCTTGGGCTTGGGCACAGCAGGTATTCCCTGACCTG 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 614 CGCCGCCGAGCTTATCAGGCAGCCTCTTGGGCTTGGGCACAGCAGGTATTCCCTGACCTG 673
Qy 481 GACCCTCAGGAGCAGCTCTACAAGGCCTATACTGGCTTTGAGCAGGCGGCCCGTGCACTG 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 674 GACCCTCAGGAGCAGCTCTACAAGGCCTATACTGGCTTTGAGCAGGCGGCCCGTGCACTG 733
Qy 541 ATGGAGGATACGCTGCGGGTGGCCCAGGCACTACGGCCCCATGGACTCTGGGGCTTCTAT 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 734 ATGGAGGATACGCTGCGGGTGGCCCAGGCACTACGGCCCCATGGACTCTGGGGCTTCTAT 793
Qy 601 CACTACCCAGCCTGTGGCAATGGCTGGCATAGTATGGCTTCCAACTATACCGGCCGCTGC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 794 CACTACCCAGCCTGTGGCAATGGCTGGCATAGTATGGCTTCCAACTATACCGGCCGCTGC 853
Qy 661 CATGCAGCCACCCTTGCCCGCAACACTCAACTGCATTGGCTCTGGGCCGCCTCCAGTGCC 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 854 CATGCAGCCACCCTTGCCCGCAACACTCAACTGCATTGGCTCTGGGCCGCCTCCAGTGCC 913
Qy 721 CTCTTCCCCAGCATCTACCTCCCACCCAGGCTGCCACCTGCCCACCACCAGGCCTTTGTC 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 914 CTCTTCCCCAGCATCTACCTCCCACCCAGGCTGCCACCTGCCCACCACCAGGCCTTTGTC 973
Qy 781 CGACATCGCCTGGAGGAGGCCTTCCGTGTGGCCCTTGTTGGGCACCGACATCCCCTGCCT 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 974 CGACATCGCCTGGAGGAGGCCTTCCGTGTGGCCCTTGTTGGGCACCGACATCCCCTGCCT 1033
Qy 841 GTCCTGGCCTATGTCCGCCTCACACACCGGAGATCTGGGAGGTTCCTGTCCCAGGATGAC 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1034 GTCCTGGCCTATGTCCGCCTCACACACCGGAGATCTGGGAGGTTCCTGTCCCAGGATGAC 1093
Qy 901 CTTGTGCAGTCCATTGGTGTGAGTGCAGCACTAGGGGCAGCCGGCGTGGTGCTCTGGGGG 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1094 CTTGTGCAGTCCATTGGTGTGAGTGCAGCACTAGGGGCAGCCGGCGTGGTGCTCTGGGGG 1153
Qy 961 GACCTGAGCCTCTCCAGCTCTGAGGAGGAGTGCTGGCATCTCCATGACTACCTGGTGGAC 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1154 GACCTGAGCCTCTCCAGCTCTGAGGAGGAGTGCTGGCATCTCCATGACTACCTGGTGGAC 1213
Qy 1021 ACCTTGGGCCCCTATGTGATCAATGTGACCAGGGCAGCGATGGCCTGCAGTCACCAGCGG 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1214 ACCTTGGGCCCCTATGTGATCAATGTGACCAGGGCAGCGATGGCCTGCAGTCACCAGCGG 1273
Qy 1081 TGCCATGGCCACGGGCGCTGTGCCCGGCGAGATCCAGGACAGATGGAAGCCTTTCTACAC 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1274 TGCCATGGCCACGGGCGCTGTGCCCGGCGAGATCCAGGACAGATGGAAGCCTTTCTACAC 1333
Qy 1141 CTGTGGCCAGACGGCAGCCTTGGAGATTGGAAGTCCTTCAGCTGCCACTGTTACTGGGGC 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1334 CTGTGGCCAGACGGCAGCCTTGGAGATTGGAAGTCCTTCAGCTGCCACTGTTACTGGGGC 1393
Qy 1201 TGGGCTGGCCCCACCTGCCAGGAGCCCAGCCTGGGCCTAAAGAAGCAGTATAAAGCCAGG 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1394 TGGGCTGGCCCCACCTGCCAGGAGCCCAGCCTGGGCCTAAAGAAGCAGTATAAAGCCAGG 1453
Qy 1261 GCCCCTGCCACTGCCTCTTCTTTTCCCTGCTGCCACTTTTCCAGTCCTGGAACTACTCTG 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1454 GCCCCTGCCACTGCCTCTTCTTTTCCCTGCTGCCACTTTTCCAGTCCTGGAACTACTCTG 1513
Qy 1321 TCCCACTCTTGCTCTATTCAGTTTACAGTCAACCCTCCCAAGCACACACCCCGCTTCCCT 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1514 TCCCACTCTTGCTCTATTCAGTTTACAGTCAACCCTCCCAAGCACACACCCCGCTTCCCT 1573
Qy 1381 TGGAATCCCTGA 1392
||||||||||||
Db 1574 TGGAATCCCTGA 1585
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of Pardi, Frost, Turner, Kuhn, Weismann, and WO917 with the mRNA sequences encoding HYAL of WO774 or NCBI for the benefit of producing mRNA encoding human or bovine HYAL. One would have been motivated to do so with a reasonable expectation of success because WO917 and Webb taught that HYAL breaks down the ECM to promote delivery of nucleic acids and WO917 and WO774 teach administering an mRNA encoding HYAL; WO917 teaches administering a bovine HYAL, and WO774 and NCBI teach sequences encoding bovine and human HYAL. One would have been motivated to do so with a reasonable expectation of success because WO917 teaches the HYAL used in their methods can be a PH20, including bovine or human PH20 and WO774 and NCBI teach bovine and human PH20. Since SEQ ID NO 190 and the NCBI sequence for human HYAL comprise 100% identity to claimed SEQ ID NOs 10 and 12, modifying the methods of Pardi, Frost, Turner, Kuhn, Weismann, and WO917 with the mRNA sequences of WO774 or NCBI would have produced all the limitations of Claim 7.
Claim(s) 1, 6, 10, 12-14, 22-23, 27, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Pardi, Frost, Turner, Kuhn, Weismann, and WO917 as applied to claims 1, 6, 10, 12-14, 22-23 and 40 above, and further in view of WO2013/151774 (published on 10 October 2013, “WO774”, of record), US Patent No. 9052312 (issued on 09 June 2015, “US312”, of record), and Athey (et al. 2017. A new and updated resource for codon usage tables. BMC Bioinformatics 18:391, “Athey”, of record).
All references are of record.
This rejection has been updated in response to the claim amendments.
NOTE: page # references in WO documents refer to the PDF page #.
The teachings of Pardi, Frost, Turner, Kuhn, Weismann, and WO917 as applicable to Claim(s) 1, 6, 10, 12-14, 22-23, and 40 have been described in the 103 rejection above.
Pardi, Frost, Turner, Kuhn, Weismann, and WO917 teach a method for subcutaneous mRNA delivery to a subject comprising injecting into a subject’s subcutaneous tissue a first formulation comprising a plurality of LNPs that encapsulate a hyaluronidase-encoding mRNA (which would result in the hyaluronidase encoded by the mRNA being expressed and degrading the ECM, thereby increasing exposure to the subject’s circulatory system) and then subsequently injecting to the same subcutaneous tissue a separate, second formulation of a plurality of LNPs encapsulating a therapeutic (or other, nonhyaluronidase-encoding, or “non-helper”) mRNA (wherein the second LNPs would enter the subject’s circulatory system due to the hyaluronidase’s degradation of the ECM).
WO917 teaches (p. 10 L25-30) the HYAL used in their methods can be a PH20, including bovine or human PH20. Weismann teaches (§Coding sequence ¶2) mRNA for therapies can be codon optimized to improve translation. A person of ordinary skill in the art knows—and Weismann indicates (same §, ¶2)—the genetic code is degenerate.
Pardi, Frost, Turner, Kuhn, Weismann, and WO917 do not teach the HYAL mRNA comprises an amino acid (AA) sequence comprises SEQ ID NOs 11 or 13 (Claim 27).
Regarding Claim 27: However, WO774, drawn to a combination therapy comprising an anti-HA agent and another therapeutic agent, teaches a sequence for bovine HYAL comprising 100% sequence identity to claimed SEQ ID NO 11, as shown by the following alignment:
ID BAV41106 standard; protein; 553 AA.
XX
AC BAV41106;
XX
DT 05-DEC-2013 (first entry)
XX
DE Bos taurus hyaluronidase PH20 precursor, SEQ 11.
XX
KW EC 3.2.1.35; Hyaluronidase PH20; SPAM1; breast tumor; cancer;
KW chemotherapy; colon tumor; cytostatic; head and neck tumor; lung tumor;
KW ovary tumor; pancreas tumor; prostate tumor; protein therapy;
KW solid tumor; sperm surface protein PH20; therapeutic;
KW uterine cervix tumor.
XX
OS Bos taurus.
XX
CC PN WO2013151774-A1.
XX
CC PD 10-OCT-2013.
XX
CC PF 15-MAR-2013; 2013WO-US032684.
XX
PR 04-APR-2012; 2012US-0686429P.
PR 16-OCT-2012; 2012US-0714719P.
XX
CC PA (HALO-) HALOZYME INC.
XX
CC PI Maneval DC, Shepard HM, Thompson CB;
XX
DR WPI; 2013-Q86216/70.
XX
CC PT Combination useful for treating cancer e.g. solid tumor, pancreatic
CC PT cancer, ovarian cancer, lung cancer, colon cancer, prostate cancer
CC PT comprises composition containing anti-hyaluronan agent; and composition
CC PT containing tumor-targeted taxane.
XX
CC PS Disclosure; SEQ ID NO 11; 230pp; English.
XX
CC The present invention relates to a novel composition, useful for treating
CC cancer in an individual. The composition comprises a composition
CC containing anti-hyaluronan agent, and a composition containing tumor-
CC targeted taxane, where the anti-hyaluronic agent is hyaluronidase enzyme.
CC The hyaluronidase used can be bacterial hyaluronidase (EC 4.2.2.1 or EC
CC 4.2.99.1), hyaluronidase from leeches, other parasites and crustaceans
CC (EC 3.2.1.36) and mammalian-type hyaluronidase (EC 3.2.1.35). The
CC invention further discloses a method for treating a cancer by
CC administering the above combination composition. The composition is used
CC as a combination for treating a cancer e.g., tumor, solid tumor, tumor
CC having increased cellular and/or stromal expression of hyaluronan,
CC compared to a non-cancerous tissue of the same tissue type or compared to
CC a non-metastatic tumor of the same tumor-type, pancreatic cancer, ovarian
CC cancer, lung cancer, colon cancer, prostate cancer, cervical cancer, head
CC and neck cancer and breast cancer. The combination of anti-hyaluronan
CC agent and tumor-targeted taxane shows synergistic effect for treating
CC cancer i.e., the combination results in a significantly improved efficacy
CC on tumor growth inhibition compared to the individual treatments at the
CC same dose. The anti-hyaluronan agent degrades tumor-associated
CC hyaluronan, and tumor-targeted taxane achieves intratumoral delivery. The
CC tumor-targeted taxane formulation reduces intratumoral nucleoside
CC deaminase protein levels or protein activity compared to the levels or
CC activity of the nucleoside deaminase in the absence of the intratumoral
CC taxane formulation. The combination composition increases the
CC intratumoral activity of a nucleoside analog. The present sequence
CC represents a Bos taurus hyaluronidase PH20 (also known as SPAM1 or sperm
CC surface protein PH20), an anti-hyaluronic agent used in the novel
CC composition of the invention.
XX
SQ Sequence 553 AA;
Query Match 100.0%; Score 2966; Length 553;
Best Local Similarity 100.0%;
Matches 553; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MRMLRRHHISFRSFAGSSGTPQAVFTFLLLPCCLALDFRAPPLISNTSFLWAWNAPVERC 60 SEQ ID NO 11
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MRMLRRHHISFRSFAGSSGTPQAVFTFLLLPCCLALDFRAPPLISNTSFLWAWNAPVERC 60 WO774 SEQ ID NO 11
Qy 61 VNRRFQLPPDLRLFSVKGSPQKSATGQFITLFYADRLGYYPHIDEKTGKTVFGGIPQLGN 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VNRRFQLPPDLRLFSVKGSPQKSATGQFITLFYADRLGYYPHIDEKTGKTVFGGIPQLGN 120
Qy 121 LKSHMEKAKNDIAYYIPNDSVGLAVIDWENWRPTWARNWKPKDVYRDESVELVLQKNPQL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LKSHMEKAKNDIAYYIPNDSVGLAVIDWENWRPTWARNWKPKDVYRDESVELVLQKNPQL 180
Qy 181 SFPEASKIAKVDFETAGKSFMQETLKLGKLLRPNHLWGYYLFPDCYNHNHNQPTYNGNCP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SFPEASKIAKVDFETAGKSFMQETLKLGKLLRPNHLWGYYLFPDCYNHNHNQPTYNGNCP 240
Qy 241 DVEKRRNDDLEWLWKESTALFPSVYLNIRLKSTQNAALYVRNRVQEAIRLSKIASVESPL 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 DVEKRRNDDLEWLWKESTALFPSVYLNIRLKSTQNAALYVRNRVQEAIRLSKIASVESPL 300
Qy 301 PVFVYARPVFTDGSSTYLSQGDLVNSVGEIVSLGASGIIMWGSLNLSLSMQSCMNLGTYL 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 PVFVYARPVFTDGSSTYLSQGDLVNSVGEIVSLGASGIIMWGSLNLSLSMQSCMNLGTYL 360
Qy 361 NTTLNPYIINVTLAAKMCSQVLCHNEGVCTRKHWNSSDYLHLNPMNFAIQTGEGGKYTVP 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 NTTLNPYIINVTLAAKMCSQVLCHNEGVCTRKHWNSSDYLHLNPMNFAIQTGEGGKYTVP 420
Qy 421 GTVTLEDLQKFSDTFYCSCYANIHCKKRVDIKNVHSVNVCMAEDICIDSPVKLQPSDHSS 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GTVTLEDLQKFSDTFYCSCYANIHCKKRVDIKNVHSVNVCMAEDICIDSPVKLQPSDHSS 480
Qy 481 SQEASTTTFSSISPSTTTATVSPCTPEKHSPECLKVRCSEVIPNVTQKACQSVKLKNISY 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 SQEASTTTFSSISPSTTTATVSPCTPEKHSPECLKVRCSEVIPNVTQKACQSVKLKNISY 540
Qy 541 QSPIQNIKNQTTY 553
|||||||||||||
Db 541 QSPIQNIKNQTTY 553
US312, drawn to biotechnologies related to diagnostic criteria, teaches (Col 11 L20-25 and Table 1 [starts Col 13]) SEQ ID NO 95, which is an AA sequence of HYAL and is over 99% identical to claimed SEQ ID NO 13, as shown by the following alignment:
US-12-740-166-95
(NOTE: this sequence has 2 duplicates in the database searched)
Sequence 95, US/12740166
Patent No. 9052312
GENERAL INFORMATION
APPLICANT: Max-Planck-Gesellschaft zur Foerderung der Wissenschaften eV
TITLE OF INVENTION: Biomarker for the prediction of responsiveness to an anti-Tumour
TITLE OF INVENTION: Necrosis Factor alpha (TNF) treatment
FILE REFERENCE: N3102 PCT BLN
CURRENT APPLICATION NUMBER: US/12/740,166
CURRENT FILING DATE: 2010-04-28
PRIOR APPLICATION NUMBER: EP 07 11 9810.5
PRIOR FILING DATE: 2007-10-31
NUMBER OF SEQ ID NOS: 122
SEQ ID NO 95
LENGTH: 462
TYPE: PRT
ORGANISM: Human
Query Match 99.4%; Score 2588.5; Length 462;
Best Local Similarity 99.8%;
Matches 462; Conservative 0; Mismatches 0; Indels 1; Gaps 1;
Qy 1 MTTQLGPALVLGVALCLGCGQPLPQVPERPFSVLWNVPSAHCEARFGVHLPLNALGIIAN 60 SEQ ID NO 13
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTTQLGPALVLGVALCLGCGQPLPQVPERPFSVLWNVPSAHCEARFGVHLPLNALGIIAN 60 US312 SEQ ID NO 95
Qy 61 RGQHFHGQNMTIFYKNQLGLYPYFGPRGTAHNGGIPQALPLDRHLALAAYQIHHSLRPGF 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RGQHFHGQNMTIFYKNQLGLYPYFGPRGTAHNGGIPQALPLDRHLALAAYQIHHSLRPGF 120
Qy 121 AGPAVLDWEEWCPLWAGNWGRRRAYQAASWAWAQQVFPDLDPQEQLYKAYTGFEQAARAL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 AGPAVLDWEEWCPLWAGNWGRRRAYQAASWAWAQQVFPDLDPQEQLYKAYTGFEQAARAL 180
Qy 181 MEDTLRVAQALRPHGLWGFYHYPACGNGWHSMASNYTGRCHAATLARNTQLHWLWAASSA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 MEDTLRVAQALRPHGLWGFYHYPACGNGWHSMASNYTGRCHAATLARNTQLHWLWAASSA 240
Qy 241 LFPSIYLPPRLPPAHHQAFVRHRLEEAFRVALVGHRHPLPVLAYVRLTHRRSGRFLSQDD 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LFPSIYLPPRLPPAHHQAFVRHRLEEAFRVALVGHRHPLPVLAYVRLTHRRSGRFLSQDD 300
Qy 301 LVQSIGVSAALGAAGVVLWGDLSLSSSEEECWHLHDYLVDTLGPYVINVTRAAMACSHQR 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 LVQSIGVSAALGAAGVVLWGDLSLSSSEEECWHLHDYLVDTLGPYVINVTRAAMACSHQR 360
Qy 361 CHGHGRCARRDPGQMEAFLHLWPDGSLGDWKSFSCHCYWGWAGPTCQEPSLGLKKQYKAR 420
||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||
Db 361 CHGHGRCARRDPGQMEAFLHLWPDGSLGDWKSFSCHCYWGWAGPTCQEP-LGLKKQYKAR 419
Qy 421 APATASSFPCCHFSSPGTTLSHSCSIQFTVNPPKHTPRFPWNP 463
|||||||||||||||||||||||||||||||||||||||||||
Db 420 APATASSFPCCHFSSPGTTLSHSCSIQFTVNPPKHTPRFPWNP 462
The information provided at Col 11 L20-25 and Table 1 indicates SEQ ID NO 95 is an AA sequence of human HYAL.
Furthermore, Athey teaches (§Abstract-Background) recombinant gene technologies commonly codon optimize an mRNA, meaning they replace codons with synonymous ones in order to increase protein expression. Athey teaches (p. 7 ¶1) a protein that was codon optimized for clinical gene therapy, indicating mRNAs are codon optimized for use in gene therapy. The entire Athey reference is directed to databases and references that can be used (e.g., §Abstract-Conclusion) for codon optimizing.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of Pardi, Frost, Turner, Kuhn, Weismann, and WO917 with the bovine or human AA HYAL sequences of WO774 or US312 and the teachings of Weismann and Athey for the benefit of producing mRNA encoding codon optimized human or bovine HYAL, wherein translation will be optimized when it is used in clinical gene therapy.
One would have been motivated to do so with a reasonable expectation of success because WO917 and Webb taught that HYAL breaks down the ECM to promote delivery of nucleic acids and WO917 teaches administering an mRNA encoding HYAL; WO917 teaches administering a human or bovine HYAL, WO774 and US312 teach sequences encoding bovine and human HYAL; and Weismann and Athey teach benefits of codon optimization and tools for codon optimizing. One would have been motivated to do so with a reasonable expectation of success because WO917 teaches the HYAL used in their methods can be a PH20, including bovine or human PH20, and WO774 and US312 teach AA sequences of bovine and human PH20. The teachings of Weissman and Athey indicate that coding an AA sequence as mRNA was known and commonly used in the art. Since WO774 SEQ ID NO 11 comprises 100% identity to claimed SEQ ID NO 11, modifying the methods of Pardi, Frost, Turner, Kuhn, Weismann, and WO917 with the AA sequences of WO774 or US 312 and teachings of Athey would have produced all the limitations of Claim 27.
Claim(s) 1, 6, 10, 12-14, 22-24, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Pardi, Frost, Turner, Kuhn, Weismann, and WO917 as applied to claims 1, 6, 10, 12-14, 22-23, and 40 above, and further in view of United States Patent Application Publication No. US 2016/0367638 (published 22 December 2016, “US638”, of record).
All references are of record.
NOTE: page # references in WO documents refer to the PDF page #.
This rejection is maintained and updated in response to the claim amendments.
The teachings of Pardi, Frost, Turner, Kuhn, Weismann, and WO917 as applicable to Claim(s) 1, 6, 10, 12-14, 22-23, and 40 have been described in the 103 rejection above.
Pardi, Frost, Turner, Kuhn, Weismann, and WO917 teach a method for subcutaneous mRNA delivery to a subject comprising injecting into a subject’s subcutaneous tissue a first formulation comprising a plurality of LNPs that encapsulate a hyaluronidase-encoding mRNA (which would result in the hyaluronidase encoded by the mRNA being expressed and degrading the ECM, thereby increasing exposure to the subject’s circulatory system) and then subsequently injecting to the same subcutaneous tissue a separate, second formulation of a plurality of LNPs encapsulating a therapeutic (or other, nonhyaluronidase-encoding, or “non-helper”) mRNA (wherein the second LNPs would enter the subject’s circulatory system due to the hyaluronidase’s degradation of the ECM).
As discussed above, WO917 teaches (p. 119 L9-25) liposomes interact with cells via different mechanisms and varying the liposome formulation can alter which mechanism is operative.
Pardi, Frost, Turner, Kuhn, Weismann, and WO917 do not teach that the first formulation (i.e., helper mRNA) is delivered to the subject at a dose of at least 0.5 mg/kg of body weight of the subject (Claim 24). Pardi, Frost, Turner, Kuhn, Weismann, and WO917 do not teach that the delivery agents for transfection include DOTAP (Claim 37).
Regarding Claim 24: However, US638, drawn to cationic LNP compositions encapsulating protein-encoding mRNA, teaches (Table 19, starts after ¶279) subcutaneously administering 2 mg/kg mRNA. US638 describes (¶238-239, Fig. 5) that dose led to an effective amount of protein product in mouse plasma. Therefore, US638 teaches administering mRNA to a subject at a dose of at least 0.5 mg/kg of body weight.
Regarding Claim 37: US638 teaches (¶90) delivery agents for transfection can include DOTAP.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer each of the LNP formulations of Pardi, Frost, Turner, Kuhn, Weismann, and WO917 (wherein the LNP comprising HYAL-encoding mRNA is administered before the other LNP comprising a non-HYAL mRNA) at the doses of at least 2 mg/kg body weight of US638 for the benefit of administering mRNA-encapsulating LNP at doses that are routine and conventional in the art. One would have been motivated to do so with a reasonable expectation of success because US638 observed successful protein translation from mRNA-encapsulating LNPs that were subcutaneously administered at those doses.
Furthermore, it is settled law that determining a dose is routine: “[C]onducting clinical trials to test for an optimal dose for a drug ‘is generally a routine process[‘].” Eli Lilly and Co. v. Teva Pharmaceuticals USA, Inc., 619 F.3d 1329, 1342 (Fed. Cir. 2010). “In Mayo, the application of the natural law was merely routine optimization of drug dosage to maximize therapeutic effect.” Ariosa Dignostics, Inc. v. Sequenom, Inc., 809 F.3d 1282, 1293 (Fed. Cir. 2015) (Dyk, J., concurring).
It would have been obvious to include the delivery agent DOTAP for the benefit of testing different lipid formulations to determine which lipid formulations produce cell entry by the most efficacious mechanism and the benefit of fine-tuning the delivery system depending on target cell or tissue type. One would have been motivated to do so with a reasonable expectation of success because WO917 teaches liposomes interact with cells via different mechanisms and that varying liposome formulation can alter which mechanism(s) is operative. That would have motivated an artisan to formulate LNPs comprising any lipid, including DOTAP.
Therefore, the limitations of Claims 24 and 37 would have been obvious in view of Pardi, Frost, Turner, Kuhn, Weismann, WO917, and US638.
Claim(s) 1, 6, 10, 12-14, 18-19, 22-23, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Pardi, Frost, Turner, Kuhn, Weismann, and WO917 as applied to claims 1, 6, 10, 12-14, 22-23, and 40 above, and further in view of United States Patent No. 4252118 (published 24 February 1981, “US118”).
US118 is a newly applied reference.
This rejection is new in response to the claim amendments.
The teachings of Pardi, Frost, Turner, Kuhn, Weismann, and WO917 as applicable to Claim(s) 1, 6, 10, 12-14, 22-23, and 40 have been described in the 103 rejection above.
Pardi, Frost, Turner, Kuhn, Weismann, and WO917 teach a method for subcutaneous mRNA delivery to a subject comprising injecting into a subject’s subcutaneous tissue a first formulation comprising a plurality of LNPs that encapsulate a hyaluronidase-encoding mRNA (which would result in the hyaluronidase encoded by the mRNA being expressed and degrading the ECM, thereby increasing exposure to the subject’s circulatory system) and then subsequently injecting to the same subcutaneous tissue a separate, second formulation of a plurality of LNPs encapsulating a therapeutic (or other, nonhyaluronidase-encoding, or “non-helper”) mRNA (wherein the second LNPs would enter the subject’s circulatory system due to the hyaluronidase’s degradation of the ECM).
As discussed above, WO917 and the combination of references make obvious separate administration of a first formula comprising LNPs encapsulating a hyaluronidase-encoding mRNA and subsequent administration of a second formula comprising LNPs encapsulating a different mRNA.
Pardi, Frost, Turner, Kuhn, Weismann, and WO917 do not teach that the first formulation is injected with a first syringe and the second formulation is injected with a second syringe that is different from the first syringe (Claim 18) or that each syringe is prefilled for a single subcutaneous injection (Claim 19).
Regarding Claims 18 and 19: However, US118, drawn to a non-reusable prefilled syringe for a single administration of a drug solution, teaches (§Abstract) a non-reusable prefilled syringe for a single administration of a drug solution. US118 teaches (Col 1-2 L40-15) the invention provides a nonreusable syringe that is prefilled with a suitable drug to provide for measured, predosed doses of drug for dispensing a drug, which provides an easily dispensable dose of drug that a patient can self-administer. US118 teaches (Col 5 L65-end and Col 8 L45-60) their syringe is suitable for subcutaneous drug administration and allows injection by untrained nonprofessionals.
As discussed in the preceding 103 rejections, following the treatment regimen of Pardi, Frost, Turner, Kuhn, Weismann, and WO917 would have required a first subcutaneous injection with LNPs encapsulating hyaluronidase-encoding mRNA and a subsequent subcutaneous injection with LNPs encapsulating a therapeutic gene-encoding mRNA.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate each of the two LNP formulations of Pardi, Frost, Turner, Kuhn, Weismann, and WO917 by placing a suitable dose of the first LNP formulation inside of a first US118 single-use syringe for subcutaneous administration and by placing a suitable dose of the second LNP formulation inside of a second US118 single-use syringe for subsequent subcutaneous administration. One would have been motivated to do so with a reasonable expectation of success because US118 teaches their single-use syringes are suitable for subcutaneous administration and because US118 and Frost teach that subcutaneous administration offers benefits including that patients can administer their own drug which (Frost, § 1.2 Strategies to overcome the limitations of the extracellular matrix ¶4) can improve health-related quality of life. One would have been motivated to do so because US118 teaches (Col 8 L45-60) prefilled syringes, and an artisan would have readily understood that supplying a patient with single-use, prefilled syringes would have made it easier to self-administer a drug at the proper dose and would remove the potential error of reusing a syringe.
Despite the fact that US118 doesn’t teach anything about mRNA drugs, an artisan would have understood that US118’s syringe could be used to supply any drug in liquid form, and it would have been a simple matter to swap any mRNA drug for US118’s heparin drug.
Therefore, the limitations of Claims 18-19 would have been obvious in view of Pardi, Frost, Turner, Kuhn, Weismann, WO917, and US118.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
NOTE: all of the NDSP rejections are obviousness rejections. The broad instant claims would have been obvious over any patented or copending application that claims any mRNA that is or can be a therapeutic mRNA, in view of the prior art. The prior art teaches why it is beneficial to administer HYAL before administering another drug and all of the patented or copending applications teach some form of mRNA that is or can be a therapeutic mRNA, and that is if they do not explicitly claim HYAL or OTC. Applicant is advised to provide clear explanation how these inventions aren’t obvious over each other.
Claims 1, 6-7, 10, 12-14, 18-19, 22-24, 27, 37, and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patents or Copending Applications as shown in the table below, in view of Pardi (et al. 2015. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Control. Releas. 217[10]:345-351, “Pardi”, of record), Frost (2007. Recombinant human hyaluronidase (rHuPH20): an enabling platform for subcutaneous drug and fluid administration. Expert Opin. Drug Deliv. 4[4]:427-440, “Frost”, of record on IDS), Turner (and Balu-Iyer. 11 Jan 2018. Challenges and Opportunities for the Subcutaneous Delivery of Therapeutic Proteins. J. Pharmaceut. Sci 107:1247-1260, “Turner”, of record), Kuhn (et al. 2012. mRNA as a Versatile Tool for Exogenous Protein Expression. Curr. Gene Ther. 12:347-361, “Kuhn”, of record), Weissman (2014. mRNA transcript therapy. Expert Rev. Vaccin. 14[2]:265-281, “Weissman”, of record), International Publication Number WO917 (published 22 October 2009, of record), WO2013/151774 (published on 10 October 2013, “WO774”, of record), US Patent No. 9052312 (issued on 09 June 2015, “US312”, of record), Athey (et al. 2017. A new and updated resource for codon usage tables. BMC Bioinformatics 18:391, “Athey”, of record), United States Patent Application Publication No. US 2016/0367638 (published 22 December 2016, “US638”, of record), and United States Patent No. 4252118 (published 24 February 1981, “US118”).
This rejection has been updated in response to the claim amendments.
US Patent No. or Copending Application No.
Document #
Claims
10975369
All (1-16)
10808241
All
11497716
1-25
17/320946
US 20210353556
All besides canceled
17/130114
US 20210180041
All besides canceled
18/328206
US 20240041789
All besides canceled
19/650695
All
19/677899
US20260272838
All
19/792174
All
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The instant claims are drawn to a method for subcutaneous delivery of two mRNAs: an mRNA encoding a HYAL and a therapeutic mRNA that can be for remediating OTC deficiency (which encompasses an mRNA encoding OTC protein), and wherein the mRNAs may be encapsulated in LNPs including LNPs comprising cationic lipids including the cationic lipid HGT4003.
The patented or copending claims are drawn to methods for purifying mRNA or methods of encapsulating mRNA including an mRNA encoding OTC protein and/or a HYAL protein.
All claims sets are directed to mRNAs encoding OTC protein and/or a HYAL protein or broadly to encapsulating mRNAs.
The patented or copending claims do not all recite certain features of the instant claims (including the timepoints of administering the mRNAs and the location of mRNA expression, and subcutaneous administration) but those features are taught by the prior art.
Pardi (§Abstract, §3.Results-3.2. mRNA-LNP administration into mice, entire §; §4. Discussion ¶5; §5. Conclusion; §1. Introduction ¶3-4; §2. Material and methods-2.4. Formulation of the mRNA ¶2; §4. Discussion ¶2), Frost (§Abstract; §1.2 Strategies to overcome the limitations of the extracellular matrix ¶1-4; §1.1 The extracellular matrix as a physiological barrier to drug delivery, entire §; §1.2 Strategies to overcome the limitations of the extracellular matrix, final ¶; §1.3 Hyaluronidases: from spreading factors to the human genome ¶2-3; §2. The development of rHuPH20, an rDNA-derived human hyaluronidase enzyme, entire § and §3. Development of Hylenex, recombinant [hyaluronidase human injection], entire §, including §-3.1.1 Hypodermoclysis and §-3.1.4 Absorption of radiopaque agents; §5. Expert opinion, entire §; §2.2 Development of a manufacturing process for rHuPH20, entire §), Turner (§Immune response to therapeutic proteins ¶1; §Formulation Excipients and Additives ¶1-2; §Abstract), Kuhn (§Abstract, §Introduction ¶2; §PRECLINICAL AND CLINICAL APPLICATIONS OF RNA-Induction of Antigen-Specific Immune Responses ¶6; §mRNA-Based Gene Therapy, entire §), Weissman (§Introduction ¶2; §Protein replacement therapies ¶1-2; §Coding sequence ¶2), WO917 (pp. 2-3 L30-5; p. 2 L24-31; p. 3 L13-16; p. 6 L10-16; p. 7 L10-15; p. 6 L14-16; pp. 118-119 L10-25; p. 119 L9-25; p. 6 L24-31; p.10 L1-10; p. 155 §3. Use as a spreading agent and p. 158 §6. Gene therapy applications; WO917 p. 80 L5-16; p. 10 L25-30), WO774 (p. 3 L10-15; p. 25 L15-20, SEQ ID NO 190), NCBI (HYAL mRNA sequence), WO774 (SEQ ID NO 11), US312 (Col 11 L20-25 and Table 1 [starts Col 13]; SEQ ID NO 95), Athey (§Abstract-Background, p. 7 ¶1, §Abstract-Conclusion), US638 (Table 19, starts after ¶279; ¶238-239, Fig. 5; ¶90), and US118 (§Abstract, Col 1-2 L40-15, Col 5 L65-end and Col 8 L45-60) teach the elements of the instant claims not recited in the patented or copending claims, including sequences comprising the claimed SEQ ID NOs, as explained in the 103 rejection above.
Therefore, it would have been obvious to an artisan before the effective filing date of the instant invention to modify the patented or copending claims with the teachings and sequences of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, NCBI, WO774, US312, Athey, US638, and US118 for the benefits of breaking down the ECM to facilitate drug delivery and additional benefits of using mRNA instead of protein (since mRNA is less expensive) and avoiding insertional mutagenesis.
An artisan would have been motivated to use subcutaneous administration because that method is conducive to slower release which would have been beneficial towards breaking down the ECM (see WO917 p. 159 L10-20). The limitations about the syringe and dosing would have been obvious in view of US118, US638, and Pardi, for benefits of making the LNPs easy to administer safely. One would have been motivated to do so with a reasonable expectation of success because effective doses of mRNA were known.
Therefore, the instant claims would have been obvious in view of the patented or copending claims and the teachings of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, NCBI, WO774, US312, Athey, US638, and US118, and using the instant methods would require the composition/methods of the patented or copending claims. It would not be possible to use the instant methods without the methods of producing mRNA or methods of encapsulating mRNA of the patented/copending claims.
The rejections over copending applications are provisional nonstatutory double patenting rejections.
Claims 1, 6-7, 10, 12-14, 18-19, 22-24, 27, 37, and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent Nos. as shown in the table below in view of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, US312, Athey, US638, and US118.
This rejection has been updated in response to the claim amendments.
US Patent No.
Claims
11547666
2-22
11530298
14-22
10961184
13-20
11427535
5-14
10507183
1-3
11234936
1-18
11400109
1-17
11167043
1-4
10137087
1-22
10786455
1-18
10835583
1-18
10065919
2-23
10766852
1-18
9629804
1-18
10266559
1-18
10822368
1-17
9956271
1-9
11135274
1-3
11890377
all
10266843
All
12318489
All
12239735
All
12331005
All
10238754
1-10
12102720
10
10702478
All
11124804
All
12459885
1-19
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The instant claims are drawn to a method for subcutaneous delivery of two mRNAs: an mRNA encoding a HYAL and a therapeutic mRNA that can be for remediating OTC deficiency (which encompasses an mRNA encoding OTC protein), and wherein the mRNAs may be encapsulated in LNPs including LNPs comprising cationic lipids including the cationic lipid HGT4003.
The patented claims are drawn to a composition comprising an mRNA encoding a protein wherein the mRNA is encapsulated by a form of LNP, wherein the mRNA may be an mRNA encoding OTC protein and/or a HYAL protein or to methods of treating OTC deficiency.
Both claims sets are directed to LNPs encapsulating protein-encoding mRNAs wherein the mRNA can encode any mRNA including an OTC protein and/or a HYAL protein.
The patented claims do not all recite certain features of the instant claims (including the timepoints of administering the mRNAs and the location of mRNA expression, and subcutaneous administration) but those features are taught by the prior art.
Pardi (§Abstract, §3.Results-3.2. mRNA-LNP administration into mice, entire §; §4. Discussion ¶5; §5. Conclusion; §1. Introduction ¶3-4; §2. Material and methods-2.4. Formulation of the mRNA ¶2; §4. Discussion ¶2), Frost (§Abstract; §1.2 Strategies to overcome the limitations of the extracellular matrix ¶1-4; §1.1 The extracellular matrix as a physiological barrier to drug delivery, entire §; §1.2 Strategies to overcome the limitations of the extracellular matrix, final ¶; §1.3 Hyaluronidases: from spreading factors to the human genome ¶2-3; §2. The development of rHuPH20, an rDNA-derived human hyaluronidase enzyme, entire § and §3. Development of Hylenex, recombinant [hyaluronidase human injection], entire §, including §-3.1.1 Hypodermoclysis and §-3.1.4 Absorption of radiopaque agents; §5. Expert opinion, entire §; §2.2 Development of a manufacturing process for rHuPH20, entire §), Turner (§Immune response to therapeutic proteins ¶1; §Formulation Excipients and Additives ¶1-2; §Abstract), Kuhn (§Abstract, §Introduction ¶2; §PRECLINICAL AND CLINICAL APPLICATIONS OF RNA-Induction of Antigen-Specific Immune Responses ¶6; §mRNA-Based Gene Therapy, entire §), Weissman (§Introduction ¶2; §Protein replacement therapies ¶1-2; §Coding sequence ¶2), WO917 (pp. 2-3 L30-5; p. 2 L24-31; p. 3 L13-16; p. 6 L10-16; p. 7 L10-15; p. 6 L14-16; pp. 118-119 L10-25; p. 119 L9-25; p. 6 L24-31; p.10 L1-10; p. 155 §3. Use as a spreading agent and p. 158 §6. Gene therapy applications; WO917 p. 80 L5-16; p. 10 L25-30), WO774 (p. 3 L10-15; p. 25 L15-20, SEQ ID NO 190), NCBI (HYAL mRNA sequence), WO774 (SEQ ID NO 11), US312 (Col 11 L20-25 and Table 1 [starts Col 13]; SEQ ID NO 95), Athey (§Abstract-Background, p. 7 ¶1, §Abstract-Conclusion), US638 (Table 19, starts after ¶279; ¶238-239, Fig. 5; ¶90), and US118 (§Abstract, Col 1-2 L40-15, Col 5 L65-end and Col 8 L45-60) teach the elements of the instant claims not recited in the patented or copending claims, including sequences comprising the claimed SEQ ID NOs, as explained in the 103 rejection above.
Therefore, it would have been obvious to an artisan before the effective filing date of the instant invention to modify the patented claims with the teachings and sequences of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, NCBI, WO774, US312, Athey, US638, and US118 for the benefits of breaking down the ECM to facilitate drug delivery and additional benefits of using mRNA instead of protein (since mRNA is less expensive) and avoiding insertional mutagenesis.
An artisan would have been motivated to use subcutaneous administration because that method is conducive to slower release which would have been beneficial towards breaking down the ECM (see WO917 p. 159 L10-20). The limitations about the syringe and dosing would have been obvious in view of US118, US638, and Pardi, for benefits of making the LNPs easy to administer safely. One would have been motivated to do so with a reasonable expectation of success because effective doses of mRNA were known.
Therefore, the instant claims would have been obvious in view of the patented claims and the teachings of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, NCBI, WO774, US312, Athey, US638, and US118, and using the instant methods would require the composition/methods of the patented claims. It would not be possible to use the instant methods without the methods of producing mRNA or methods of encapsulating mRNA of the patented claims.
Claims 1, 6-7, 10, 12-14, 18-19, 22-24, 27, 37, and 40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application Nos. as shown in the table below in view of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, US312, Athey, US638, and US118.
NOTE: page # references in WO documents refer to the PDF page #.
This rejection has been updated in response to the claim amendments.
Copending Application No.
Document
Claims
17/998589
US 20230226219
5-21
17/619040
US 20230092238
57-69
17/291937
US 20230071228
131-144
17/295621
US 20230050672
17-27
17/054886
US 20220323355
68-83
17/608347
US 20220257724
32-42
17/605343
US 20220233444
21-31
17/614096
US 20220226244
16-28
17/604244
US 20220177423
20-30
17/291919
US 20220071905
52-62
17/291923
US 20220016029
55-65
17/057929
US 20220008338
121-139
17/058557
US 20210213140
All besides canceled
17/058574
US 20210206739
All besides canceled
16/966214
US 20210113483
69-89
17/841194
(notice of allowance mailed)
US 20230065040
All besides canceled
17/448996
US 20220072152
All besides canceled
17/094327
US 20210205421
All besides canceled
15/482431
US 20170314041
All besides canceled
16/983121
US 20210009503
All besides canceled
18/431597
US 20240342307
All besides canceled
18/545858
US 20240293319
All besides canceled
18/458767
US 20240148651
All besides canceled
18/815955
US 20240408020
All
18/890983
US 20250145577
All besides canceled
18/910694
US 20250049954
82-86
19/027390
All besides canceled
19/027437
All besides canceled
19/233547
All besides canceled
19/351909
US20260125339
All
19/414473
US20260207505
Claim 12 and claims depending therefrom
19/475932
US20260294818
All
19/726150
All
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The instant claims are drawn to a method for subcutaneous delivery of two mRNAs: an mRNA encoding a HYAL and a therapeutic mRNA that can be for remediating OTC deficiency (which encompasses an mRNA encoding OTC protein), and wherein the mRNAs may be encapsulated in LNPs including LNPs comprising cationic lipids including the cationic lipid HGT4003.
The copending claims are drawn to a composition comprising an mRNA encoding a protein wherein the mRNA is encapsulated by a form of LNP, wherein the mRNA may be an mRNA encoding OTC protein and/or a HYAL protein or to methods of treating OTC deficiency or to methods of using encapsulated mRNAs.
All claims sets are directed to LNPs encapsulating protein-encoding mRNAs wherein the mRNA explicitly encodes an OTC or HYAL or can encode any mRNA including OTC protein and/or a HYAL protein.
The copending claims do not all recite certain features of the instant claims (including the timepoints of administering the mRNAs and the location of mRNA expression, and subcutaneous administration) but those features are taught by the prior art.
Pardi (§Abstract, §3.Results-3.2. mRNA-LNP administration into mice, entire §; §4. Discussion ¶5; §5. Conclusion; §1. Introduction ¶3-4; §2. Material and methods-2.4. Formulation of the mRNA ¶2; §4. Discussion ¶2), Frost (§Abstract; §1.2 Strategies to overcome the limitations of the extracellular matrix ¶1-4; §1.1 The extracellular matrix as a physiological barrier to drug delivery, entire §; §1.2 Strategies to overcome the limitations of the extracellular matrix, final ¶; §1.3 Hyaluronidases: from spreading factors to the human genome ¶2-3; §2. The development of rHuPH20, an rDNA-derived human hyaluronidase enzyme, entire § and §3. Development of Hylenex, recombinant [hyaluronidase human injection], entire §, including §-3.1.1 Hypodermoclysis and §-3.1.4 Absorption of radiopaque agents; §5. Expert opinion, entire §; §2.2 Development of a manufacturing process for rHuPH20, entire §), Turner (§Immune response to therapeutic proteins ¶1; §Formulation Excipients and Additives ¶1-2; §Abstract), Kuhn (§Abstract, §Introduction ¶2; §PRECLINICAL AND CLINICAL APPLICATIONS OF RNA-Induction of Antigen-Specific Immune Responses ¶6; §mRNA-Based Gene Therapy, entire §), Weissman (§Introduction ¶2; §Protein replacement therapies ¶1-2; §Coding sequence ¶2), WO917 (pp. 2-3 L30-5; p. 2 L24-31; p. 3 L13-16; p. 6 L10-16; p. 7 L10-15; p. 6 L14-16; pp. 118-119 L10-25; p. 119 L9-25; p. 6 L24-31; p.10 L1-10; p. 155 §3. Use as a spreading agent and p. 158 §6. Gene therapy applications; WO917 p. 80 L5-16; p. 10 L25-30), WO774 (p. 3 L10-15; p. 25 L15-20, SEQ ID NO 190), NCBI (HYAL mRNA sequence), WO774 (SEQ ID NO 11), US312 (Col 11 L20-25 and Table 1 [starts Col 13]; SEQ ID NO 95), Athey (§Abstract-Background, p. 7 ¶1, §Abstract-Conclusion), US638 (Table 19, starts after ¶279; ¶238-239, Fig. 5; ¶90), and US118 (§Abstract, Col 1-2 L40-15, Col 5 L65-end and Col 8 L45-60) teach the elements of the instant claims not recited in the patented or copending claims, including sequences comprising the claimed SEQ ID NOs, as explained in the 103 rejection above.
Therefore, it would have been obvious to an artisan before the effective filing date of the instant invention to modify the copending claims with the teachings and sequences of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, NCBI, WO774, US312, Athey, US638, and US118 for the benefits of breaking down the ECM to facilitate drug delivery and additional benefits of using mRNA instead of protein (since mRNA is less expensive) and avoiding insertional mutagenesis.
An artisan would have been motivated to use subcutaneous administration because that method is conducive to slower release which would have been beneficial towards breaking down the ECM (see WO917 p. 159 L10-20). The limitations about the syringe and dosing would have been obvious in view of US118, US638, and Pardi, for benefits of making the LNPs easy to administer safely. One would have been motivated to do so with a reasonable expectation of success because effective doses of mRNA were known.
Therefore, the instant claims would have been obvious in view of the copending claims and the teachings of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, NCBI, WO774, US312, Athey, US638, and US118, and using the instant methods would require the composition/methods of the copending claims.
These are provisional nonstatutory double patenting rejections.
Claims 1, 6-7, 10, 12-14, 18-19, 22-24, 27, 37, and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patents or Copending Applications as shown in the table below, in view of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, US312, Athey, US638, and US118.
NOTE: page # references in WO documents refer to the PDF page #.
This rejection has been updated in response to the claim amendments.
US Patent No. or Copending Application No.
Document #
Claims
11254936
All (1-11)
17/572260
US 20220411791
All besides canceled
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The instant claims are drawn to a method for subcutaneous delivery of two mRNAs: an mRNA encoding a HYAL and a therapeutic mRNA that can be for remediating OTC deficiency (which encompasses an mRNA encoding OTC protein), and wherein the mRNAs may be encapsulated in LNPs including LNPs comprising cationic lipids including the cationic lipid HGT4003.
The patented or copending claims are drawn to methods of modulating polynt resistance including a resistant mRNA, or to compositions comprising nuclease resistant mRNAs, and wherein the resistant mRNA encodes OTC protein and/or a HYAL protein. All claims sets are directed to mRNAs encoding OTC protein and/or a HYAL protein or broadly to resistant mRNAs.
The patented or copending claims do not all recite certain features of the instant claims (including the timepoints of administering the mRNAs and the location of mRNA expression, and subcutaneous administration) but those features are taught by the prior art.
Pardi (§Abstract, §3.Results-3.2. mRNA-LNP administration into mice, entire §; §4. Discussion ¶5; §5. Conclusion; §1. Introduction ¶3-4; §2. Material and methods-2.4. Formulation of the mRNA ¶2; §4. Discussion ¶2), Frost (§Abstract; §1.2 Strategies to overcome the limitations of the extracellular matrix ¶1-4; §1.1 The extracellular matrix as a physiological barrier to drug delivery, entire §; §1.2 Strategies to overcome the limitations of the extracellular matrix, final ¶; §1.3 Hyaluronidases: from spreading factors to the human genome ¶2-3; §2. The development of rHuPH20, an rDNA-derived human hyaluronidase enzyme, entire § and §3. Development of Hylenex, recombinant [hyaluronidase human injection], entire §, including §-3.1.1 Hypodermoclysis and §-3.1.4 Absorption of radiopaque agents; §5. Expert opinion, entire §; §2.2 Development of a manufacturing process for rHuPH20, entire §), Turner (§Immune response to therapeutic proteins ¶1; §Formulation Excipients and Additives ¶1-2; §Abstract), Kuhn (§Abstract, §Introduction ¶2; §PRECLINICAL AND CLINICAL APPLICATIONS OF RNA-Induction of Antigen-Specific Immune Responses ¶6; §mRNA-Based Gene Therapy, entire §), Weissman (§Introduction ¶2; §Protein replacement therapies ¶1-2; §Coding sequence ¶2), WO917 (pp. 2-3 L30-5; p. 2 L24-31; p. 3 L13-16; p. 6 L10-16; p. 7 L10-15; p. 6 L14-16; pp. 118-119 L10-25; p. 119 L9-25; p. 6 L24-31; p.10 L1-10; p. 155 §3. Use as a spreading agent and p. 158 §6. Gene therapy applications; WO917 p. 80 L5-16; p. 10 L25-30), WO774 (p. 3 L10-15; p. 25 L15-20, SEQ ID NO 190), NCBI (HYAL mRNA sequence), WO774 (SEQ ID NO 11), US312 (Col 11 L20-25 and Table 1 [starts Col 13]; SEQ ID NO 95), Athey (§Abstract-Background, p. 7 ¶1, §Abstract-Conclusion), US638 (Table 19, starts after ¶279; ¶238-239, Fig. 5; ¶90), and US118 (§Abstract, Col 1-2 L40-15, Col 5 L65-end and Col 8 L45-60) teach the elements of the instant claims not recited in the patented or copending claims, including sequences comprising the claimed SEQ ID NOs, as explained in the 103 rejection above.
Therefore, it would have been obvious to an artisan before the effective filing date of the instant invention to modify the patented or copending claims with the teachings and sequences of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, NCBI, WO774, US312, Athey, US638, and US118 for the benefits of breaking down the ECM to facilitate drug delivery and additional benefits of using mRNA instead of protein (since mRNA is less expensive) and avoiding insertional mutagenesis.
An artisan would have been motivated to use subcutaneous administration because that method is conducive to slower release which would have been beneficial towards breaking down the ECM (see WO917 p. 159 L10-20). The limitations about the syringe and dosing would have been obvious in view of US118, US638, and Pardi, for benefits of making the LNPs easy to administer safely. One would have been motivated to do so with a reasonable expectation of success because effective doses of mRNA were known.
Therefore, the instant claims would have been obvious in view of the patented or copending claims and the teachings of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, NCBI, WO774, US312, Athey, US638, and US118, and using the instant methods would require the composition/methods of the patented or copending claims. The patented/copending modified mRNAs encoding HYAL/OTC could be used in the instant methods.
The rejection over the copending application is a provisional nonstatutory double patenting rejection.
Claims 1, 6-7, 10, 12-14, 18-19, 22-24, 27, 37, and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patents or Copending Applications as shown in the table below, in view of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, US312, Athey, US638, and US118.
NOTE: page # references in WO documents refer to the PDF page #.
This rejection has been updated in response to the claim amendments.
US Patent No. or Copending Application No.
Document #
Claims
17/923470
US 20230181619
All besides canceled
17/449679
US 20220160827
All besides canceled
17/923839
US 20230190954
All besides canceled
17/275803
US 20230145188
All besides canceled
16/961187
US 20210052706
61-135
16/286423
US 20190192690
All besides canceled
17/002460
US 20210196633
All besides canceled
17/292673
US 20220016265
All besides canceled
18/186856
US 20240024516
All besides canceled
17/556978
US 20220111071
All besides canceled
16/002903
US 20180272005
16-31
16/002897
US 20180272004
6-31
16/002889
US 20180272003
6-31
16/002878
US 20180272002
12-29
17/465287
US 20220054602
1-20
17/382757
US 20220048867
All besides canceled
18/295150
All besides canceled
18/295159
US 20230330262
All besides canceled
10052284
all
10493031
1-12
11447520
11-21
9061021
1-14
9956271
all
10959953
1-7, 9-20, 22-24
10138213
6
11104652
all
10022455
2, 6-7
8853377
All
10143758
1-30
19/027559
US20250257090
All
19/399536
US20260167944
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The instant claims are drawn to a method for subcutaneous delivery of two mRNAs: an mRNA encoding a HYAL and a therapeutic mRNA that can be for remediating OTC deficiency (which encompasses an mRNA encoding OTC protein), and wherein the mRNAs may be encapsulated in LNPs including LNPs comprising cationic lipids including the cationic lipid HGT4003.
The patented or copending claims are drawn to codon optimized therapeutic mRNAs or mRNAs encoding various proteins, or to methods of delivering OTC RNA or mRNA to a cell, wherein the mRNA can encode hyaluronidase or another therapeutic protein. All claims sets are broadly directed to mRNAs encoding therapeutic proteins or that encode OTC.
The patented or copending claims do not all recite certain features of the instant claims (including the timepoints of administering the mRNAs and the location of mRNA expression, and subcutaneous administration) but those features are taught by the prior art.
Pardi (§Abstract, §3.Results-3.2. mRNA-LNP administration into mice, entire §; §4. Discussion ¶5; §5. Conclusion; §1. Introduction ¶3-4; §2. Material and methods-2.4. Formulation of the mRNA ¶2; §4. Discussion ¶2), Frost (§Abstract; §1.2 Strategies to overcome the limitations of the extracellular matrix ¶1-4; §1.1 The extracellular matrix as a physiological barrier to drug delivery, entire §; §1.2 Strategies to overcome the limitations of the extracellular matrix, final ¶; §1.3 Hyaluronidases: from spreading factors to the human genome ¶2-3; §2. The development of rHuPH20, an rDNA-derived human hyaluronidase enzyme, entire § and §3. Development of Hylenex, recombinant [hyaluronidase human injection], entire §, including §-3.1.1 Hypodermoclysis and §-3.1.4 Absorption of radiopaque agents; §5. Expert opinion, entire §; §2.2 Development of a manufacturing process for rHuPH20, entire §), Turner (§Immune response to therapeutic proteins ¶1; §Formulation Excipients and Additives ¶1-2; §Abstract), Kuhn (§Abstract, §Introduction ¶2; §PRECLINICAL AND CLINICAL APPLICATIONS OF RNA-Induction of Antigen-Specific Immune Responses ¶6; §mRNA-Based Gene Therapy, entire §), Weissman (§Introduction ¶2; §Protein replacement therapies ¶1-2; §Coding sequence ¶2), WO917 (pp. 2-3 L30-5; p. 2 L24-31; p. 3 L13-16; p. 6 L10-16; p. 7 L10-15; p. 6 L14-16; pp. 118-119 L10-25; p. 119 L9-25; p. 6 L24-31; p.10 L1-10; p. 155 §3. Use as a spreading agent and p. 158 §6. Gene therapy applications; WO917 p. 80 L5-16; p. 10 L25-30), WO774 (p. 3 L10-15; p. 25 L15-20, SEQ ID NO 190), NCBI (HYAL mRNA sequence), WO774 (SEQ ID NO 11), US312 (Col 11 L20-25 and Table 1 [starts Col 13]; SEQ ID NO 95), Athey (§Abstract-Background, p. 7 ¶1, §Abstract-Conclusion), US638 (Table 19, starts after ¶279; ¶238-239, Fig. 5; ¶90), and US118 (§Abstract, Col 1-2 L40-15, Col 5 L65-end and Col 8 L45-60) teach the elements of the instant claims not recited in the patented or copending claims, including sequences comprising the claimed SEQ ID NOs, as explained in the 103 rejection above.
Therefore, it would have been obvious to an artisan before the effective filing date of the instant invention to modify the patented or copending claims with the teachings and sequences of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, NCBI, WO774, US312, Athey, US638, and US118 for the benefits of breaking down the ECM to facilitate drug delivery and additional benefits of using mRNA instead of protein (since mRNA is less expensive) and avoiding insertional mutagenesis.
An artisan would have been motivated to use subcutaneous administration because that method is conducive to slower release which would have been beneficial towards breaking down the ECM (see WO917 p. 159 L10-20). The limitations about the syringe and dosing would have been obvious in view of US118, US638, and Pardi, for benefits of making the LNPs easy to administer safely. One would have been motivated to do so with a reasonable expectation of success because effective doses of mRNA were known.
Therefore, the instant claims would have been obvious in view of the patented or copending claims and the teachings of Pardi, Frost, Turner, Kuhn, Weissman, WO917, WO774, NCBI, WO774, US312, Athey, US638, and US118, and using the instant methods would require the composition/methods of the patented or copending claims. The patented/copending mRNAs or therapeutic mRNAs or LNPs encapsulating mRNA could be used as the therapeutic mRNA of the instant methods.
The rejections over copending applications are provisional nonstatutory double patenting rejections.
Response to Arguments
Applicant's arguments filed 01 June 2026 have been fully considered but they are not persuasive. Each rejection is addressed below. Arguments that are no longer relevant are not addressed.
Objections
Claim 19 is objected to for minor informalities.
103
Applicant argues against the 103 rejections on pp. 7-12.
Applicant’s arguments with respect to claim(s) 1, 6, 10, 12-14, 22-23, and 27 (pp. 8-9) have been considered but are moot because the updated ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Specifically, all of Applicant’s arguments pertain solely to the WO196 reference, and that reference has been eliminated from the rejection.
Regarding the claim amendments requiring the LNPs encapsulating a helper mRNA encoding a hyaluronidase being the only LNPs in the first formulation and the LNPs encapsulating a non-helper mRNA being the only LNPs in the second formulation, the Pardi reference (now applied as the primary reference) teaches subcutaneous administration of mRNA formulations comprising solely LNPs that encapsulate mRNA, not any other LNPs. Therefore, all the limitations of the amended claims are met.
In response to applicant's statements about the number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991).
Furthermore, it is routine in the biotechnological arts for a person of ordinary skill to be familiar with hundreds, thousands, or even tens of thousands of references, and for such an artisan to synthesize, combine, or modify knowledge and teachings from any number of those references.
Finally, regarding the arguments on pp. 9-12, those arguments are not persuasive because they are all against the primary reference WO196 and that reference has been eliminated from the rejections.
NSDP
The arguments against the NSDP rejections are not persuasive for the same reasons the arguments against the 103 rejections are not persuasive. Therefore, the NSDP rejections must be maintained.
Conclusion
Claims 1, 6-7, 10, 12-14, 18-19, 22-24, 27, 37, and 40 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUTHIE S ARIETI whose telephone number is (571)272-1293. The examiner can normally be reached M-Th 10AM-6PM, alternate Fridays 9AM-4PM (ET).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram R Shukla can be reached on (571)272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
RUTHIE S ARIETI
Examiner
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636
Prosecution Insights