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, and 37 are pending.
Status of the Application
Applicant’s response and amendment filed 08 December 2025 are acknowledged and entered.
Applicant has amended Claims 1, 7, 10, 12-14, 18-19, 22-24, and 27.
Response to Amendment
Applicant has amended Claims 1, 24, and 27 to overcome the 112(a) written description (WD) rejections; the 112(a) WD rejection is withdrawn.
Applicant has amended Claims 1 and 18 to overcome the 112(b) rejections; the previous 112(b) rejections are withdrawn.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.
Claims 1, 6-7, 10, 12-14, 18-19, 22-24, 27, and 37 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Rejections not reiterated here are withdrawn.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 Objections
Claims 1 and 23 are objected to because of the following informalities:
The last part of Claim 1 part (i) should remove from the subcutaneous tissue and instead read: …thereby increase exposure to the subject's circulatory system; and... The current construction is redundant.
Claim 23 should remove within because [something] is injected within 1-6 hours of [something else] or [something] is injected 1-6 hours prior to [something else]. The construction within 1-6 hours prior is messy.
Appropriate correction is required.
REJECTIONS NECESSITATED BY AMENDMENT
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 19 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection. This rejection is new.
The instant specification, as well as the PCT and/or provisional specifications to which the instant application claims priority, as originally filed does not provide support for the invention as now claimed: wherein the first syringe and the second syringe are each single use (Claim 19). The specification does not provide sufficient "blazemarks", nor direction for the claimed method encompassing the above-mentioned limitations, as currently recited.
Specifically, the specification does not disclose any single use first and second syringes. The Spec. teaches (¶__) a prefilled syringe that is prefilled for a single subcutaneous administration but doesn’t teach anything about a single use syringe.
Thus, the instant claims now recite limitations which were not disclosed in the specification as-filed, and now change the scope of the instant disclosure as-filed. Such limitations recited in the present claims, which did not appear in of the instant specification, nor in the PCT and/or provisional application(s) to which priority is claimed, introduce new concepts and violate the description requirement of the first paragraph of 35 U.S.C. § 112. Applicant is required to remove the new matter from their claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 24 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173. In the present instance, Claim 24 recites: a dose equivalent for producing at least 1U of the hyaluronidase per mg of the non-helper mRNA and the non-helper mRNA is delivered to the subject at a dose of at least 0.5 mg/kg of body weight of the subject. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is not clear what constitutes a dose equivalent for producing at least 1U of the hyaluronidase per mg of the non-helper mRNA and the non-helper mRNA is delivered to the subject at a dose of at least 0.5 mg/kg of body weight of the subject. The art of Math Study Strategies (2000. Math for Nursing International Units (U) for Medication. Available online at avc.edu. Accessed on 24 February 2026, “Math”) teaches some medications are measured in International Units which is a unit [that] measures the medication’s action not its weight. The Spec. discloses (¶77) in some embodiments, an International Unit for hyaluronidase may be defined as the activity of 0.1 mg of the International Standard Preparation. Although that description describes a single embodiment, it does not disclose any particular dose for producing at least 1U of hyaluronidase. Nothing in that description discloses what dose of mRNA is equivalent for producing at least 1U of the hyaluronidase. Furthermore, there is no evidence that the diverse spectrum of subject bodies encompassed by the claim produce any predictable amount of hyaluronidase from an amount of mRNA. Nothing in the claims or Spec. clarifies what is an amount equivalent for producing at least 1U of hyaluronidase. Therefore an artisan would not understand the metes and bounds of the claim.
In the interest of compact prosecution the claim is interpreted as requiring a dose of HYAL-encoding mRNA at least 0.005 mg/kg body weight.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 22 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 22 depends from Claim 1 and recites: The method of claim 1, wherein the. Claim 1 already recites that the first formulation is injected prior to injecting the second formulation because it recites:
… injecting a first formulation into subcutaneous tissue of the subject, wherein:
the first formulation comprises a first lipid nanoparticle encapsulating a helper mRNA encoding a hyaluronidase;
the hyaluronidase encoded by the helper mRNA is expressed within the subcutaneous tissue of the subject; and
extracellular matrices of the subcutaneous tissue are degraded by enzymatic action of the hyaluronidase to thereby increase exposure to the subject's circulatory system from the subcutaneous tissue; and
injecting a separate second formulation into the same subcutaneous tissue of the subject, wherein:
the second formulation comprises a second lipid nanoparticle encapsulating a non-helper mRNA; and
the second lipid nanoparticle is exposed to and enters the subject's circulatory system due to degradation of the extracellular matrices of the subcutaneous tissue by the enzymatic action of the hyaluronidase. [emphasis added.]
The second formulation is injected after injection of the first formulation and after the first formulation’s product degrades the ECM. The second step of the method necessarily occurs after the outcome of the first step has occurred because the second step relies on the outcome of the first step (i.e., degradation of the ECM). Therefore Claim 22 doesn’t change the scope of Claim 1 or further limit Claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
REJECTIONS MAINTAINED AND 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, 12-14, 22-23, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO196 (published on 18 September 2014, of record), Webb (1952. Effect of hyaluronidase on rate of absorption of subcutaneous fluids. AMA Archiv. Surg. 65[5]:770-773, “Webb”, of record), 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 (published 31 October 2014, of record), and International Publication Number WO917 (published 22 October 2009, of record). NOTE: page # references in WO documents refer to the PDF page #. All references of record. This rejection has been updated in response to the claim amendments.
WO196 is drawn to synergistic enhancement of nucleic acid expression via blended LNP formulations. WO196 teaches (¶6) pharmaceutical compositions comprising a blend of lipid nanoparticles (LNPs) wherein the LNPs comprise or encapsulate one or more polynucleotides (polynts) such as mRNA. WO196 teaches (same ¶) the blended LNP compositions enhance expression of the encapsulated polynt(s), including enhancing production of polypeptide(s) encoded by the polynt(s).
WO196 teaches (¶14) the LNPs can encapsulate one or more [polynt] and that such polynt can be mRNA polynts which produce functional polypeptide(s) or protein(s). WO196 teaches (¶86) that the delivery of one or more encapsulated polynts to one or more target cells [is] to treat a single disorder or deficiency, wherein each such polynt functions by a different mechanism of action.
WO196 teaches that (¶7) blended LNPs refers to blended lipid—not blended polynt—formulations:
As used herein, the term “blend”, “blended”, or grammatical equivalent, refers to a combination of two or more separate, non-identical formulations. Typically, the two or more separate, non-identical formulations are combined or blended into one composition, such as, a suspension, as depicted, for example, in FIG. 1. As used herein, non-identical formulations refer to formulations containing at least one distinct lipid component. In some embodiments, non-identical formulations suitable for blend contain at least one distinct cationic lipid component. The term “blend” as used herein is distinguishable from the terms “mix” or “mixture”, which are used herein to define a single formulation containing multiple non-identical cationic/ionizable lipids, multiple non-identical helper lipids, and/or multiple nonidentical PEGylated lipids. In some embodiments, a “mix” formulation contains at least two or more non-identical cationic/ionizable lipids. Typically, a “mix” formulation contains a single homogeneous population of lipid nanoparticles. [emphasis added.]
WO196 further clarifies that it is the blend of lipids that (¶5) synergistically enhances mRNA expression because the blend of LNP can comprise only a single polynt. WO196 teaches it is the blend of LNPs—not the blend of polynt or simultaneous administration of polynt—that increases mRNA expression. Descriptions at ¶9-15 and subsequent passages indicate that WO196’s invention is synergistic enhancement of enhancement due to different lipid formulations—not among two or more polynt delivered together. To that point, WO196 teaches (¶9):
In certain embodiments, the blended first lipid nanoparticle and second lipid nanoparticle comprise the same one or more polynucleotides, wherein the expression of the one or more polynucleotides by the target cells following the administration (e.g., intravenously) of the blended pharmaceutical composition to a subject exceeds the relative sum of the expression of the one or more polynucleotides achieved by the first lipid nanoparticle and the expression of the one or more polynucleotides achieved by the second lipid nanoparticle when the first lipid nanoparticle and the second lipid nanoparticle are administered to the subject independently of each other. [emphasis added.]
WO196 continues (¶11), teaching that the blend of LNPs enhances expression of even a single polynt compared to when the polynt is delivered with a nonblended LNP:
In another embodiment, only one of the two or more lipid nanoparticles that comprise the blended composition comprises or encapsulates a polynucleotide. For example, where the pharmaceutical compositions comprises two blended lipid nanoparticles, only the first lipid nanoparticle comprises one or more polynucleotides while the second lipid nanoparticle does not comprise a polynucleotide (i.e., the second polynucleotide [sic] is empty). In such an embodiment, following the administration (e.g., intravenously) of the two blended first and second lipid nanoparticles that comprise the pharmaceutical composition to the subject, the production of one or more polypeptides or proteins encoded by the encapsulated polynucleotides by a target cell is enhanced relative to the production of one or more polypeptides or proteins observed when the first lipid nanoparticle is administered to the subject independently of the second lipid nanoparticle. [emphasis added.]
WO196 continues (¶12-15) the same explanation: it is the blend of LNPs that results in unexpectedly improve expression of mRNA. WO196 teaches (¶37) their “blend” or “blended” formulation comprises two or more different [LNPs] whereas a “mix” or “mixture” describes a pharmaceutical formulation or composition that includes only a single lipid nanoparticle in the formulation… the terms mix and mixture… refer to a pharmaceutical composition comprising only a single population of [LNP], [which] have the same or substantially the same lipid composition.
Further demonstrating the point that WO196 teaches administering blended nonidentical LNP particles, ¶38 teaches blended LNP compositions improve subsequent transfection of polynt:
The blended lipid nanoparticle compositions are characterized as being able to efficiently deliver the encapsulated polynucleotides to target cells, and are also characterized by their ability to improve the subsequent transfection of such encapsulated polynucleotides following contacting one or more target cells… The blended lipid nanoparticle compositions described herein are also characterized by their ability to enhance (e.g., increase) the production of one or more polypeptides or proteins (e.g., by target cells) encoded by one or more polynucleotides encapsulated in such nanoparticle compositions. [emphasis added.]
All of those teachings indicate that WO196 teaches their blend of LNPs can comprise only a single polynt, and merely administering the polynt within a blend of LNPs enhances expression.
WO196 teaches (¶22) embodiments wherein one of the encapsulated polynts can encode a functional ornithine transcarbamylase (OTC) and one of the polynts can comprise mRNA encod[ing]…hyaluronidase. WO196 teaches (¶123) the LNP-encapsulated polynts encode functional proteins or enzymes that are excreted or secreted by one or more target cells into the surrounding extracellular fluid, and encode functional proteins or enzymes such as hyaluronidase (HYAL). WO196 teaches (¶117-122) using the invention to treat OTC deficiency. WO196 teaches (¶7) that two or more separate, non-identical formulations are combined or blended into one composition, where “nonidentical formulations” refers to lipid components. Then WO196 teaches (¶8) embodiments where the polynts are mRNA encoding a functional protein, provided herein are methods of enhancing the production and/or excretion of polypeptides encoded by such polynts by a target cell. WO196 teaches (¶8) their pharmaceutical compositions can comprise a blend of two or more LNPs that can each comprise one or more polynt. That means that the pharmaceutical compositions can comprise two or more LNPs wherein each LNP encapsulates a single kind of polynt or (discussed above) wherein only one LNP encapsulates a polynt and wherein the other LNP is empty. As discussed, ¶22 taught mRNAs encoding HYAL.
WO196 teaches (p. 86 ¶2) methods of delivering a single mRNA to a subject.
Regarding Claim 10, WO196 teaches that (¶15) at least one LNP component is a cationic lipid. WO196 teaches (¶3) including a cationic lipid is beneficial because:
the positively charged cationic lipid on the outer particle surfaces facilitates the interaction of the cationic lipid-based liposome with the negatively-charged cellular membranes, thereby promoting fusion of the liposome with the cellular membrane and delivering the liposome and/or emptying the nucleic acid contents of the liposome intracellularly.
WO196 teaches (¶129) the LNPs may be administered via subcutaneous injection.
Regarding Claims 12-14: WO196 teaches (¶17) the LNPs may comprise one or more PEG-modified lipids and that (¶61) the PEG-modified phospholipid and derivatized [sic] lipids of the present invention may comprise a molar ratio from about 0% to about 20%, about 0.5% to about 20%, about 1% to about 15%, about 4% to about 10%, or about 2% of the total lipid present in a liposomal lipid nanoparticle. Those number encompass at least 1% PEG-modified lipid (out of total lipid) in the LNP. That passage also indicates that a liposomal LNP was contemplated. Therefore WO196 teaches limitations of Claims 12-14.
WO196 teaches (¶89) the polynts may be chemically modified to confer stability.
WO196 teaches (¶128) the polypeptides (such as a therapeutic protein) expressed from the LNP-encapsulated polynts may be excreted by the cell into serum and (¶172) an example wherein the expressed protein was isolated from serum; that indicates the expressed protein was detectable in serum. WO196 teaches (¶168) the synergistic increase in protein expression has been observed in the liver and will also occur in lung, kidney, CNS, and other tissues. WO196 teaches (¶67) the LNPs can concentrate in the liver.
Regarding Claim 37: WO196 teaches (¶15) the LNPs may comprise any of the following cationic lipids: C12-200, DOTAP (1,2-dioleyl-3-trimethylammonium propane), DODAP (1,2-dioleyl-3-dimethylammonium propane), DOTMA (1,2-di-0-octadecenyl-3-trimethylammonium propane), DLinDMA, DLin-KC2-DMA, HGT4003 and ICE. Those are some of the same cationic lipids recited in Claim 37.
Altogether, the teachings of WO196 teach methods of subcutaneously administering LNPs comprising mRNAs including OTC mRNA and HYAL mRNA to a subject in need (i.e., for treating OTC deficiency).
WO196 does not teach the HYAL mRNA is injected in a first formulation as a helper mRNA that expresses the HYAL, wherein the HYAL encoded by the helper mRNA is expressed and degrades, via enzymatic action of the hyaluronidase, extracellular matrices (ECM) within the subject’s subcutaneous tissue, thereby increasing exposure of the subject’s circulatory system to the subcutaneous tissue. WO196 teaches (¶38) administering the blended LNP composition to improve subsequent transfection of encapsulated polynt but doesn’t provide details on administering a separate second formulation of LNPs encapsulating a second mRNA that is different from the mRNA encoding HYAL.
However, subcutaneously injecting HYAL to improve circulatory uptake was well known within the pharmaceutical arts, and the benefits of administering mRNA to express a protein (i.e., an mRNA for expressing HYAL)—rather than administering protein directly—were also well known.
The art of Webb teaches (§Abstract) HYAL (protein) increases the rate of spread and absorption of fluid injected to subcutaneous tissues and does so via lysis of hyaluronic acid (HA) which is the cementing agent in the intercellular ground substance. Webb teaches (§Findings ¶1) HYAL increased diffusion rate of fluids administered subcutaneously to human thigh. Webb teaches (§Comment ¶1) HYAL depolymerizes hyaluronic acid/hyaluronan (HA), thereby facilitating absorption of injected fluids by increasing the available cellular membrane and number of available absorptive channels (capillaries and lymphatics). Webb discusses (same §, ¶3) a study that showed addition of testicular extract (hyaluronidase) to diphtheria antitoxin administered subcutaneously "approximately doubles the concentration of antitoxin in the blood at two and at six hours after its injection."
Webb’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.
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 the treatment comprising mRNA encapsulated within an LNP blend of WO196 with the teachings about HYAL lysing the ECM to improve circulatory uptake of fluids and fluid drugs of Webb, the teachings about advantages of subcutaneous delivery and detriments of immune response to protein therapeutics of Turner, the teachings about benefits—including immunological benefits—of mRNA therapies of Kuhn, and the teachings of Weissman about the cost benefits of mRNA therapy vs protein therapy for the benefits of improving circulatory uptake of mRNAs by breaking down the ECM and the ease and low cost of administering an mRNA therapeutic subcutaneously. It would have been obvious to administer LNP-encapsulated HYAL mRNA because LNP-encapsulated mRNA was known (i.e., WO196), because Webb teaches that HYAL lyses 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., WO196), because HYAL was known to degrade the ECM, thereby improving drug uptake by the circulatory system (Webb), 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 WO196, Webb, 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 improve uptake of any subsequently administered subcutaneously-delivered drug (including mRNA).
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to use a method for subcutaneous delivery of an mRNA to a subject, wherein the mRNA encodes a HYAL enzyme as discussed in WO196 (i.e., ¶22), the method comprising injecting a first formulation comprising an LNP blend encapsulating an mRNA encoding HYAL into the subject’s subcutaneous tissue, wherein the hyaluronidase encoded by the helper mRNA is expressed and, via enzymatic action of the hyaluronidase, degrades extracellular matrices within the subject’s subcutaneous tissue, thereby increasing exposure of the subject’s circulatory system to the subcutaneous tissue, and then injecting a second formulation comprising any drug, including a nonhelper mRNA (i.e., an mRNA encoding any gene therapy gene) into the subject’s subcutaneous tissue, wherein the drug that can be a nonhelper mRNA is exposed to and enters the subject’s circulatory system. Since WO196 teaches (¶8) their pharmaceutical compositions can comprise lipid-blended LNPs wherein each LNP encapsulates a single polynt that can be a HYAL-encoding mRNA and the other art (Webb) teaches the benefits of administering HYAL to degrade the ECM and improve uptake of a drug, and the other art (Kuhn and Weismann) teaches the benefits of administering mRNA drugs, it would have been obvious to subcutaneously inject a first formulation comprising blended LNPs encapsulating a HYAL-encoding mRNA (which would have had the outcome of expressing HYAL protein which would degrade the ECM) and a second formulation comprising a second set of blended LNPs encapsulating any drug, including another mRNA for expressing a gene therapy protein.
WO196, Webb, Turner, Kuhn, and Weismann do not explicitly teach the HYAL-encoding mRNA and the therapeutic mRNA are administered in separate formulations (Claim 1). WO196, Webb, Turner, Kuhn, and Weismann do not teach HYAL is a mammalian endo-β-N-acetyl hexosaminidase (Claim 6); the HYAL-encoding mRNA is administered prior to administering the therapeutic mRNA composition (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 WO196 and the other references do not teach. WO917 is drawn to compositions comprising a HA-degrading enzyme (such as 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 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 6: WO917 teaches (pp. 70-74 L16-26) there are various kinds of HYAL enzymes and (p. 70 L22-25) mammalian HYAL are endo-β-N-acetyl-hexosaminidases that hydrolyze a glycosidic bond of HA. WO917 provides numerous SEQ ID NOs for various mammalian HYAL.
Regarding Claims 22-23: 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”) 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 nonhelper mRNA” (i.e., second mRNA encoding any protein). Therefore WO917 teaches limitations of Claims 1 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 blended LNPs of WO196, Webb, Turner, Kuhn, and Weismann with the teachings about a specific mammalian HYAL, kinds of formulations, and instructions for order of injection of WO917 for the benefit of breaking down the ECM with mammalian HYAL to improve delivery of the LNPs containing a nonhelper mRNA inside of a mammalian subject. 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. 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 Kuhn and Weissman indicate that there are benefits to delivering mRNA vs. protein. 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. One would have been motivated to do so with a reasonable expectation of success because WO196 teaches administering mRNA in blended LNPs increases expression. Therefore modifying the methods of WO196, Webb, 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 37.
Claim(s) 1, 6, 10, 12-14, 18-19, 22-23, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over WO196, Webb, Turner, Kuhn, Weissman and WO917 as applied to Claims 1, 6, 10, 12-14, 22-23, and 37 above, and further in view of Grissinger (2013. Perilous Infection-Control Practices With Needles, Syringes, and Vials. Pharmacy & Therapeutics 38[11]:649,666, “Grissinger”). NOTE: page # references in WO documents refer to the PDF page #. All references besides Grissinger are of record. This rejection is new in response to the claim amendments.
The teachings of WO196, Webb, Turner, Kuhn, Weismann, and WO917 as applicable to Claim(s) 1, 6, 10, 12-14, 22-23, and 37 have been described in the previous 103 rejection.
A method for subcutaneous delivery of an mRNA to a subject, the method comprising:
injecting a first formulation into subcutaneous tissue of the subject, wherein:
the first formulation comprises a first lipid nanoparticle encapsulating a helper mRNA encoding a hyaluronidase;
the hyaluronidase encoded by the helper mRNA is expressed within the subcutaneous tissue of the subject; and
extracellular matrices of the subcutaneous tissue are degraded by enzymatic action of the hyaluronidase to thereby increase exposure to the subject's circulatory system from the subcutaneous tissue; and
injecting a separate second formulation into the same subcutaneous tissue of the subject, wherein:
the second formulation comprises a second lipid nanoparticle encapsulating a non-helper mRNA; and
the second lipid nanoparticle is exposed to and enters the subject's circulatory system due to degradation of the extracellular matrices of the subcutaneous tissue by the enzymatic action of the hyaluronidase
would have been obvious in view of WO196, Webb, Turner, Kuhn, Weismann, and WO917.
WO196, Webb, 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 the first and second syringes are each single use syringes (Claim 19).
However, Grissinger, drawn to perilous infection-control practices with needles, syringes, and vials, teaches (§Safe Practice Recommendations ¶2) healthcare guidelines from the CDC require one needle, one syringe, only one time and (same § ¶3) All staff members should understand that any form of syringe or needle reuse is dangerous and should be avoided. The current CDC guidelines recommend that syringes and needles be used only once. That teaching indicates that in practice, any syringe should be a single use syringe.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to administer each of the first and second formulations of WO196, Webb, Turner, Kuhn, Weismann, and WO917 with a new and separate syringe, wherein each syringe is used only once, as taught by Grissinger. One would have been motivated to do so with a reasonable expectation of success because Grissinger teaches using one needle and one syringe only one time is a standard practice in healthcare. Therefore the limitations of Claims 18-19 would have been obvious in view of WO196, Webb, Turner, Kuhn, Weismann, WO917, and Grissinger.
Claims 1, 6-7, 10, 12-14, 22-24, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over WO196, Webb, Turner, Kuhn, Weissman and WO917, as applied to Claims 1, 6, 10, 12-14, 22-23, and 37 above, and further in view of WO2013/151774 (published on 10 October 2013, “WO774”) 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”). All references of record. This rejection has been updated in response to the claim amendments.
The teachings of WO196, Webb, Turner, Kuhn, Weismann, and WO917 as applicable to Claim(s) 1, 6, 10, 12-14, 22-23, and 37 have been described in a previous 103 rejection.
A method for subcutaneous delivery of an mRNA to a subject, the method comprising:
injecting a first formulation into subcutaneous tissue of the subject, wherein:
the first formulation comprises a first lipid nanoparticle encapsulating a helper mRNA encoding a hyaluronidase;
the hyaluronidase encoded by the helper mRNA is expressed within the subcutaneous tissue of the subject; and
extracellular matrices of the subcutaneous tissue are degraded by enzymatic action of the hyaluronidase to thereby increase exposure to the subject's circulatory system from the subcutaneous tissue; and
injecting a separate second formulation into the same subcutaneous tissue of the subject, wherein:
the second formulation comprises a second lipid nanoparticle encapsulating a non-helper mRNA; and
the second lipid nanoparticle is exposed to and enters the subject's circulatory system due to degradation of the extracellular matrices of the subcutaneous tissue by the enzymatic action of the hyaluronidase
and wherein the HYAL is a mammalian endo-β-N-acetyl-hexosaminidase would have been obvious in view of WO196, Webb, Turner, Kuhn, Weismann, and WO917.
WO917 teaches (p. 10 L25-30) the HYAL used in their methods can be a PH20, including bovine or human PH20.
WO196, Webb, Turner, Kuhn, Weismann, and WO917 do not teach the HYAL mRNA comprises a polynt sequence having greater than 90% (Claim 7) or 95% (Claim 24) sequence identity with SEQ ID NOs 9, 10, or 12.
However, WO774, drawn to a combination therapy comprising an anti-HA agent and another therapeutic agent, teaches a polynt sequence with 99% or greater identity to SEQ ID NOs 9 and 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 99% identity to claimed SEQ ID NO 9 and 100% identity to claimed SEQ ID NO 10, as shown by the following alignments:
SEQ ID NO 9
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 99.0%; Score 2081; Length 2105;
Best Local Similarity 99.9%;
Matches 2103; Conservative 0; Mismatches 0; Indels 2; Gaps 2;
Qy 1 GGTTTATCTCTGTTCTTGGTGAGGAGACAGACAGAATTGACTGCTGTGCTCATCCGCGAG 60 SEQ ID NO 9
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GGTTTATCTCTGTTCTTGGTGAGGAGACAGACAGAATTGACTGCTGTGCTCATCCGCGAG 60 WO774 SEQ ID NO 190
Qy 61 GGTAAATGTGCTCAGCTCTTTATGGAGTAGTGGAGACGGGCAGAGATGACAAGATGAAGC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GGTAAATGTGCTCAGCTCTTTATGGAGTAGTGGAGACGGGCAGAGATGACAAGATGAAGC 120
Qy 121 AACTTGCAAAACATTCCTAAATACGAAGGAAGAAGAATATTTAAATG-AAATCATCATTA 179
||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||
Db 121 AACTTGCAAAACATTCCTAAATACGAAGGAAGAAGAATATTTAAATGTAAATCATCATTA 180
Qy 180 TTCATTTTTATCCATCAAAGTGGCTTCATTCTGTGTTCATATCTTGCATCAAATATTAGG 239
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TTCATTTTTATCCATCAAAGTGGCTTCATTCTGTGTTCATATCTTGCATCAAATATTAGG 240
Qy 240 TACACCAAAGCGTGTAGGAGAAAAAAGTGCCTTTCACAGTCATCGCTCTTTGTGATGAGA 299
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TACACCAAAGCGTGTAGGAGAAAAAAGTGCCTTTCACAGTCATCGCTCTTTGTGATGAGA 300
Qy 300 ATGCTGAGGCGCCACCATATCTCCTTTCGGAGCTTTGCTGGGTCTAGCGGAACACCCCAG 359
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 ATGCTGAGGCGCCACCATATCTCCTTTCGGAGCTTTGCTGGGTCTAGCGGAACACCCCAG 360
Qy 360 GCAGTGTTCACCTTCCTTCTGCTTCCGTGTTGTTTGGCTCTGGACTTCAGAGCACCCCCT 419
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GCAGTGTTCACCTTCCTTCTGCTTCCGTGTTGTTTGGCTCTGGACTTCAGAGCACCCCCT 420
Qy 420 CTTATTTCAAACACTTCTTTCCTCTGGGCCTGGAATGCCCCAGTTGAACGTTGTGTTAAC 479
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 CTTATTTCAAACACTTCTTTCCTCTGGGCCTGGAATGCCCCAGTTGAACGTTGTGTTAAC 480
Qy 480 AGAAGATTTCAACTACCTCCAGATCTGAGACTCTTCTCTGTAAAAGGAAGCCCCCAGAAA 539
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 AGAAGATTTCAACTACCTCCAGATCTGAGACTCTTCTCTGTAAAAGGAAGCCCCCAGAAA 540
Qy 540 AGTGCTACCGGACAATTTATTACATTATTTTATGCTGATAGACTTGGCTACTATCCTCAT 599
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 AGTGCTACCGGACAATTTATTACATTATTTTATGCTGATAGACTTGGCTACTATCCTCAT 600
Qy 600 ATAGATGAAAAAACAGGCAAAACCGTATTCGGAGGAATTCCCCAGTTGGGAAACTTAAAA 659
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 ATAGATGAAAAAACAGGCAAAACCGTATTCGGAGGAATTCCCCAGTTGGGAAACTTAAAA 660
Qy 660 AGTCATATGGAGAAAGCAAAAAATGACATTGCCTATTACATACCAAATGACAGCGTGGGC 719
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 AGTCATATGGAGAAAGCAAAAAATGACATTGCCTATTACATACCAAATGACAGCGTGGGC 720
Qy 720 TTGGCGGTCATTGACTGGGAAAACTGGAGGCCTACCTGGGCAAGAAACTGGAAACCTAAA 779
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 TTGGCGGTCATTGACTGGGAAAACTGGAGGCCTACCTGGGCAAGAAACTGGAAACCTAAA 780
Qy 780 GATGTTTACAGGGATGAGTCAGTTGAGTTGGTTCTGCAAAAAAATCCGCAACTCAGTTTC 839
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 GATGTTTACAGGGATGAGTCAGTTGAGTTGGTTCTGCAAAAAAATCCGCAACTCAGTTTC 840
Qy 840 CCAGAGGCTTCCAAGATTGCAAAAGTGGATTTTGAGACAGCAGGAAAGAGTTTCATGCAA 899
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 CCAGAGGCTTCCAAGATTGCAAAAGTGGATTTTGAGACAGCAGGAAAGAGTTTCATGCAA 900
Qy 900 GAGACTTTAAAACTGGGAAAATTACTTCGGCCAAATCACTTATGGGGTTATTATCTTTTT 959
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 GAGACTTTAAAACTGGGAAAATTACTTCGGCCAAATCACTTATGGGGTTATTATCTTTTT 960
Qy 960 CCTGATTGTTACAATCATAATCATAACCAACCTACTTACAATGGAAATTGCCCTGATGT- 1018
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 CCTGATTGTTACAATCATAATCATAACCAACCTACTTACAATGGAAATTGCCCTGATGTA 1020
Qy 1019 GAAAAAAGGAGAAATGATGATCTCGAGTGGTTGTGGAAGGAAAGCACTGCCCTTTTCCCT 1078
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 GAAAAAAGGAGAAATGATGATCTCGAGTGGTTGTGGAAGGAAAGCACTGCCCTTTTCCCT 1080
Qy 1079 TCTGTTTATTTGAATATCAGGTTAAAATCTACTCAAAATGCTGCCTTGTATGTTCGTAAT 1138
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 TCTGTTTATTTGAATATCAGGTTAAAATCTACTCAAAATGCTGCCTTGTATGTTCGTAAT 1140
Qy 1139 CGTGTCCAGGAAGCCATTCGGTTGTCTAAAATAGCGAGTGTCGAAAGTCCACTTCCGGTT 1198
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 CGTGTCCAGGAAGCCATTCGGTTGTCTAAAATAGCGAGTGTCGAAAGTCCACTTCCGGTT 1200
Qy 1199 TTTGTATATGCCCGTCCAGTTTTTACTGATGGGTCTTCAACATATCTTTCTCAGGGTGAC 1258
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 TTTGTATATGCCCGTCCAGTTTTTACTGATGGGTCTTCAACATATCTTTCTCAGGGTGAC 1260
Qy 1259 CTTGTGAATTCGGTTGGTGAGATCGTTTCTCTAGGTGCCTCTGGGATTATAATGTGGGGC 1318
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1261 CTTGTGAATTCGGTTGGTGAGATCGTTTCTCTAGGTGCCTCTGGGATTATAATGTGGGGC 1320
Qy 1319 AGTCTCAATCTAAGCTTATCTATGCAATCTTGCATGAACCTAGGCACTTACTTGAACACT 1378
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1321 AGTCTCAATCTAAGCTTATCTATGCAATCTTGCATGAACCTAGGCACTTACTTGAACACT 1380
Qy 1379 ACACTGAATCCTTACATAATCAACGTCACCCTAGCCGCCAAAATGTGCAGCCAAGTGCTT 1438
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1381 ACACTGAATCCTTACATAATCAACGTCACCCTAGCCGCCAAAATGTGCAGCCAAGTGCTT 1440
Qy 1439 TGCCACAATGAAGGAGTGTGTACAAGGAAACACTGGAATTCAAGCGACTATCTTCACCTG 1498
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1441 TGCCACAATGAAGGAGTGTGTACAAGGAAACACTGGAATTCAAGCGACTATCTTCACCTG 1500
Qy 1499 AACCCAATGAATTTTGCTATTCAAACTGGGGAAGGTGGAAAATACACAGTACCTGGGACA 1558
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1501 AACCCAATGAATTTTGCTATTCAAACTGGGGAAGGTGGAAAATACACAGTACCTGGGACA 1560
Qy 1559 GTCACACTTGAAGACTTGCAAAAGTTTTCTGATACATTTTATTGCAGTTGTTATGCCAAC 1618
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1561 GTCACACTTGAAGACTTGCAAAAGTTTTCTGATACATTTTATTGCAGTTGTTATGCCAAC 1620
Qy 1619 ATCCACTGTAAGAAGAGAGTTGATATAAAAAATGTTCATAGTGTTAACGTGTGTATGGCA 1678
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1621 ATCCACTGTAAGAAGAGAGTTGATATAAAAAATGTTCATAGTGTTAACGTGTGTATGGCA 1680
Qy 1679 GAAGACATTTGTATAGACAGCCCTGTGAAGTTACAACCCAGTGATCATTCCTCCAGCCAG 1738
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1681 GAAGACATTTGTATAGACAGCCCTGTGAAGTTACAACCCAGTGATCATTCCTCCAGCCAG 1740
Qy 1739 GAGGCATCTACTACCACCTTCAGCAGTATCTCACCCTCCACTACAACTGCCACAGTATCT 1798
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1741 GAGGCATCTACTACCACCTTCAGCAGTATCTCACCCTCCACTACAACTGCCACAGTATCT 1800
Qy 1799 CCATGTACTCCTGAGAAACACTCCCCTGAGTGCCTCAAAGTCAGGTGTTCGGAAGTCATC 1858
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1801 CCATGTACTCCTGAGAAACACTCCCCTGAGTGCCTCAAAGTCAGGTGTTCGGAAGTCATC 1860
Qy 1859 CCCAACGTCACCCAAAAGGCGTGTCAAAGTGTTAAATTGAAGAACATTTCCTATCAGTCA 1918
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1861 CCCAACGTCACCCAAAAGGCGTGTCAAAGTGTTAAATTGAAGAACATTTCCTATCAGTCA 1920
Qy 1919 CCTATTCAAAATATTAAAAATCAAACAACCTATTAAAATTAAATTCAGTAAAAAAAAAAA 1978
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1921 CCTATTCAAAATATTAAAAATCAAACAACCTATTAAAATTAAATTCAGTAAAAAAAAAAA 1980
Qy 1979 AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA 2038
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1981 AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA 2040
Qy 2039 AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGAAAAAAAAAA 2098
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2041 AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGAAAAAAAAAA 2100
Qy 2099 AAAAA 2103
|||||
Db 2101 AAAAA 2105
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 WO196, Webb, 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 WO196, 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 WO196, Webb, Turner, Kuhn, Weismann, and WO917 with the mRNA sequences of WO774 or NCBI would have produced all the limitations of Claim 7.
Claims 1, 6, 10, 12-14, 18-19, 22-23, 27, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over WO196 (of record), Webb, Turner, Kuhn, Weissman (of record) and International Publication Number WO917 (of record), as applied to Claims 1, 6, 10, 12-14, 22-23, and 37 above, and further in view of WO2013/151774 (published on 10 October 2013, “WO774”), US Patent No. 9052312 (issued on 09 June 2015, “US312”), and Athey (et al. 2017. A new and updated resource for codon usage tables. BMC Bioinformatics 18:391, “Athey”). All references of record. This rejection has been updated in response to the claim amendments.
The teachings of WO196, Webb, Turner, Kuhn, Weismann, and WO917 as applicable to Claim(s) 1, 6, 10, 12-14, 22-23, and 37 have been described in a previous 103 rejection.
A method for subcutaneous delivery of an mRNA to a subject, the method comprising:
injecting a first formulation into subcutaneous tissue of the subject, wherein:
the first formulation comprises a first lipid nanoparticle encapsulating a helper mRNA encoding a hyaluronidase;
the hyaluronidase encoded by the helper mRNA is expressed within the subcutaneous tissue of the subject; and
extracellular matrices of the subcutaneous tissue are degraded by enzymatic action of the hyaluronidase to thereby increase exposure to the subject's circulatory system from the subcutaneous tissue; and
injecting a separate second formulation into the same subcutaneous tissue of the subject, wherein:
the second formulation comprises a second lipid nanoparticle encapsulating a non-helper mRNA; and
the second lipid nanoparticle is exposed to and enters the subject's circulatory system due to degradation of the extracellular matrices of the subcutaneous tissue by the enzymatic action of the hyaluronidase
and wherein the HYAL is a mammalian endo-β-N-acetyl-hexosaminidase would have been obvious in view of WO196, Webb, Turner, Kuhn, Weismann, and WO917.
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.
WO196, Webb, Turner, Kuhn, Weismann, and WO917 do not teach the HYAL mRNA comprises an amino acid (AA) sequence having greater than 95% sequence identity with SEQ ID NOs 11 or 13 (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 WO196, Webb, 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 WO196 and WO917 teach 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 WO196, Webb, 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, 18-19, 22-24, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over WO196, Webb, Turner, Kuhn, Weissman and WO917 as applied to Claims 1, 6, 10, 12-14, 22-23, and 37 above, and further in view of United States Patent Application Publication No. US 2016/0367638 (published 22 December 2016, “US638”) and 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”) NOTE: page # references in WO documents refer to the PDF page #. All references besides US638 and Pardi are of record. This rejection is new in response to the claim amendments.
The teachings of WO196, Webb, Turner, Kuhn, Weismann, and WO917 as applicable to Claim(s) 1, 6, 10, 12-14, 22-23, and 37 have been described in a previous 103 rejection.
A method for subcutaneous delivery of an mRNA to a subject, the method comprising:
injecting a first formulation into subcutaneous tissue of the subject, wherein:
the first formulation comprises a first lipid nanoparticle encapsulating a helper mRNA encoding a hyaluronidase;
the hyaluronidase encoded by the helper mRNA is expressed within the subcutaneous tissue of the subject; and
extracellular matrices of the subcutaneous tissue are degraded by enzymatic action of the hyaluronidase to thereby increase exposure to the subject's circulatory system from the subcutaneous tissue; and
injecting a separate second formulation into the same subcutaneous tissue of the subject, wherein:
the second formulation comprises a second lipid nanoparticle encapsulating a non-helper mRNA; and
the second lipid nanoparticle is exposed to and enters the subject's circulatory system due to degradation of the extracellular matrices of the subcutaneous tissue by the enzymatic action of the hyaluronidase
would have been obvious in view of WO196, Webb, Turner, Kuhn, Weismann, and WO917.
WO196 teaches (¶28) mRNA doses of 30-200 µg and (p. 71, first ¶) up to 230 µg mRNA. WO196 teaches (¶127):
[the blended LNPs] may be administered and dosed in accordance with current medical practice, taking into account the clinical condition of the subject, the site and method of administration, the scheduling of administration, the subject’s age, sex, body weight and other factors relevant to clinicians of ordinary skill in the art.
WO196 teaches (same ¶): The “effective amount” for the purposes herein may be determined by such relevant considerations as are known to those of ordinary skill in experimental clinical research, pharmacological, clinical and medical arts…
WO196, Webb, Turner, Kuhn, Weismann, and WO917 do not teach that the first formulation (i.e., helper mRNA) is delivered to the subject at a dose equivalent for producing at least 1U of the HYAL per mg of the non-helper mRNA and the nonhelper RNA is delivered to the subject at a dose of at least 0.5 mg/kg of body weight of the subject (Claim 24 as interpreted, see §112b).
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.
Pardi teaches (§Abstract) injecting mice with 0.005-0.250 mg/kg doses of mRNA-LNPs by various routes and that subcutaneous injection of such doses resulted in the LNP-encapsulated mRNA being translated locally at the site of injection for up to 10 days.
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 blended LNPs of WO196, Webb, 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 0.005-2 mg/kg body weight of US638 and Pardi 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 and Pardi observed successful protein translation from mRNA-encapsulating LNPs that were subcutaneously administered at those doses. One would have been motivated to do so with a reasonable expectation of success because WO196 teaches determining a dose to administer their LNPs is a routine matter for an artisan and that artisans use various known criteria to determine a dose for a subject.
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).
Therefore the limitations of Claim 24 (as interpreted, see §112b) would have been obvious in view of WO196, Webb, Turner, Kuhn, Weismann, WO917, US638, and Pardi.
Claim(s) 1, 6, 10, 12-14, 18-19, 22-24, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over WO196, Webb, Turner, Kuhn, Weissman, WO917 US638, and Pardi as applied to Claims 1, 6, 10, 12-14, 22-24, and 37 above, and further in view of HYLENEX (2012. Highlights of Prescribing Information for HYLENEX, “Hylenex”). NOTE: page # references in WO documents refer to the PDF page #. All references besides Hylenex and others as stated above are of record. This rejection is new in response to the claim amendments.
The teachings of WO196, Webb, Turner, Kuhn, Weismann, WO917, US638, and Pardi as applicable to Claim(s) 1, 6, 10, 12-14, 22-24, and 37 have been described in the previous 103 rejection.
A method for subcutaneous delivery of an mRNA to a subject, the method comprising:
injecting a first formulation into subcutaneous tissue of the subject, wherein:
the first formulation comprises a first lipid nanoparticle encapsulating a helper mRNA encoding a hyaluronidase;
the hyaluronidase encoded by the helper mRNA is expressed within the subcutaneous tissue of the subject; and
extracellular matrices of the subcutaneous tissue are degraded by enzymatic action of the hyaluronidase to thereby increase exposure to the subject's circulatory system from the subcutaneous tissue; and
injecting a separate second formulation into the same subcutaneous tissue of the subject, wherein:
the second formulation comprises a second lipid nanoparticle encapsulating a non-helper mRNA; and
the second lipid nanoparticle is exposed to and enters the subject's circulatory system due to degradation of the extracellular matrices of the subcutaneous tissue by the enzymatic action of the hyaluronidase,
wherein the mRNA encoding HYAL is administered at a dose of at least 0.5 mg/kg and wherein the other, non-helper mRNA is administered at a dose of at least 0.5 mg/kg would have been obvious in view of WO196, Webb, Turner, Kuhn, Weismann, WO917, US638, and Pardi.
As discussed above, WO917 teaches administering HYAL before another drug and benefits for doing so. As discussed above, WO196, Webb, Turner, Kuhn, Weismann, and WO917 make obvious subcutaneously administering an LNP encapsulating HYAL-encoding mRNA to break down the extracellular matrix and improve uptake before subcutaneously administering an LNP encapsulating an mRNA encoding any protein. As discussed above, WO196, US638, and Pardi make obvious a method of administering those mRNA at a dose of at least 0.5 mg/kg.
WO196, Webb, Turner, Kuhn, Weismann, WO917, US638, and Pardi do not teach that the helper mRNA is delivered to the subject at a dose equivalent for producing at least 1U of the hyaluronidase per mg of the non-helper mRNA (Claim 24 as written) .
However, Hylenex, drawn to an information sheet for the protein drug HYLENEX, a recombinant human HYAL injection, teaches (§Dosage and Administration) subcutaneously injecting 150U HYLENEX prior to administration of subcutaneous fluid and adding up to 300U HYLENEX to another drug for subcutaneous injection. Therefore Hylenex indicates that a quantity of at least 150U of HYLENEX facilitates absorption of fluid or drug that is administered afterwards.
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 the blended LNP formulation comprising HYAL encoding mRNA of WO196, Webb, Turner, Kuhn, Weismann, WO917, US638, and Pardi (wherein the LNP comprising HYAL-encoding mRNA is administered before the other LNP comprising a non-HYAL mRNA [which is administered at 0.5 mg/kg body weight]) at an mRNA dose that would result in production of 150U-300U HYAL. One would have been motivated to do so with a reasonable expectation of success because Hylenex teaches injecting 150-300U HYLENEX and because WO196 teaches determining a dose to administer their mRNA-encapsulating LNPs is a routine matter for an artisan and that artisans use various known criteria to determine a dose for a subject.
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).
Therefore the limitations of Claim 24 (as written) would have been obvious in view of WO196, Webb, Turner, Kuhn, Weismann, WO917, US638, Pardi, and Hylenex.
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, and 37 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 International Publication Number WO196 (published 2014, of record), International Publication Number WO917 (published 2009, of record), Webb (1952. Effect of hyaluronidase on rate of absorption of subcutaneous fluids. AMA Archiv. Surg. 65[5]:770-773, “Webb”), Turner (and Balu-Iyer. 11 Jan 2018. Challenges and Opportunities for the Subcutaneous Delivery of Therapeutic Proteins. J. Pharmaceut. Sci 107:1247-1260, “Turner”), Kuhn (et al. 2012. mRNA as a Versatile Tool for Exogenous Protein Expression. Curr. Gene Ther. 12:347-361, “Kuhn”), Weissman (published 2014, of record), and WO2013/151774 (published on 10 October 2013, “WO774”), Grissinger (2013. Perilous Infection-Control Practices With Needles, Syringes, and Vials. Pharmacy & Therapeutics 38[11]:649,666, “Grissinger”), United States Patent Application Publication No. US 2016/0367638 (published 22 December 2016, “US638”), 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”), and HYLENEX (2012. Highlights of Prescribing Information for HYLENEX, “Hylenex”). NOTE: page # references in WO documents refer to the PDF page #. All references besides Grissinger, US638, Pardi, and Hylenex are of record. 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
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 WO196, WO917, and Weissman. Briefly, WO196 teaches (¶86) administering more than one polynt and (¶129) subcutaneous administration; WO917 teaches (p. 70 L22-25) mammalian HYAL are endo-β-N-acetyl-hexosaminidases, (pp. 6-7 L10-5) administering the HYAL agent and the second agent sequentially and at different timepoints in relation to one another and (p. 155 §3. Use as a spreading agent and p. 158 §6. Gene therapy applications) HYAL facilitates drug delivery including viral gene therapies; Webb teaches (§Comment ¶1-3) subcutaneously injecting a HYAL improves uptake by the circulatory system of fluids and drugs; Turner teaches (§Abstract) subcutaneous administration of drugs is cost effective and convenient and (§Immunogenicity considerations) protein therapeutics can be immunogenic; Kuhn teaches (§mRNA-based gene therapy) mRNA therapeutic can be designed to have reduced immunogenicity; and Weissman teaches (§Protein replacement therapies) the benefits of using mRNA to express a protein instead of using manufactured protein (which is expensive) or (§Introduction ¶2) a virus (because a virus can integrate into the genome and cause mutagenesis, which is not a risk of administering mRNA). Additionally, the other claim limitations are taught as follows: syringe (Grissinger, §Safe Practice Recommendations ¶2-3) and dosing (US638, Table 19, starts after ¶279; ¶238-239, Fig. 5; Pardi, §Abstract; and Hylenex, §Dosage and Administration).
WO774 teaches (p. 25 L15-20) SEQ ID NO 190, which encodes a bovine HYAL that comprises 100% identity to claimed SEQ ID NO 10, and an AA sequence for bovine HYAL comprising 100% sequence identity to claimed SEQ ID NO 11. Those alignments are shown here:
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
[truncated; see 103 rejection for complete alignment]
Qy 1621 CAGTCACCTATTCAAAATATTAAAAATCAAACAACCTATTA 1661
|||||||||||||||||||||||||||||||||||||||||
Db 1915 CAGTCACCTATTCAAAATATTAAAAATCAAACAACCTATTA 1955
SEQ ID NO 11
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
[truncated; see 103 rejection for complete alignment]
Qy 541 QSPIQNIKNQTTY 553
|||||||||||||
Db 541 QSPIQNIKNQTTY 553
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 of WO196, WO917, Webb, Turner, Kuhn, and Weissman, and sequences of WO774, 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 Grissinger, US638, Pardi, and Hylenex, for benefits of using one needle and one syringe only one time is a standard practice in healthcare, administering mRNA encapsulating LNP at doses that are routine and conventional in the art, and administering the blended LNP formulation comprising HYAL encoding mRNA at an mRNA dose that would result in production of 150U-300U HYAL. One would have been motivated to do so with a reasonable expectation of success because effective doses were known and because WO196 teaches determining a dose to administer their mRNA-encapsulating LNPs is a routine matter for an artisan and that artisans use various known criteria to determine a dose for a subject. Therefore the instant claims would have been obvious in view of the patented or copending claims and the teachings of WO196, WO917, Webb, Turner, Kuhn, WO774, Weissman, and Grissinger, US638, Pardi, and Hylenex, 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, and 37 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 WO196, WO917, Webb, Turner, Kuhn, Weissman, WO774, Grissinger, US638, Pardi, and Hylenex. NOTE: page # references in WO documents refer to the PDF page #. All references besides Grissinger, US638, Pardi, and Hylenex are of record. 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
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 WO196, WO917, and Weissman. Briefly, WO196 teaches (¶86) administering more than one polynt and (¶129) subcutaneous administration; WO917 teaches (p. 70 L22-25) mammalian HYAL are endo-β-N-acetyl-hexosaminidases, (pp. 6-7 L10-5) administering the HYAL agent and the second agent sequentially and at different timepoints in relation to one another and (p. 155 §3. Use as a spreading agent and p. 158 §6. Gene therapy applications) HYAL facilitates drug delivery including viral gene therapies; Webb teaches (§Comment ¶1-3) subcutaneously injecting a HYAL improves uptake by the circulatory system of fluids and drugs; Turner teaches (§Abstract) subcutaneous administration of drugs is cost effective and convenient and (§Immunogenicity considerations) protein therapeutics can be immunogenic; Kuhn teaches (§mRNA-based gene therapy) mRNA therapeutic can be designed to have reduced immunogenicity; and Weissman teaches (§Protein replacement therapies) the benefits of using mRNA to express a protein instead of using manufactured protein (which is expensive) or (§Introduction ¶2) a virus (because a virus can integrate into the genome and cause mutagenesis, which is not a risk of administering mRNA). Additionally, the other claim limitations are taught as follows: syringe (Grissinger, §Safe Practice Recommendations ¶2-3) and dosing (US638, Table 19, starts after ¶279; ¶238-239, Fig. 5; Pardi, §Abstract; and Hylenex, §Dosage and Administration).
WO774 teaches (p. 25 L15-20) SEQ ID NO 190, which encodes a bovine HYAL that comprises 100% identity to claimed SEQ ID NO 10, and an AA sequence for bovine HYAL comprising 100% sequence identity to claimed SEQ ID NO 11. Those alignments are shown 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 of WO196, WO917, Webb, Turner, Kuhn, and Weissman, and sequences of WO774, 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 Grissinger, US638, Pardi, and Hylenex, for benefits of using one needle and one syringe only one time is a standard practice in healthcare, administering mRNA encapsulating LNP at doses that are routine and conventional in the art, and administering the blended LNP formulation comprising HYAL encoding mRNA at an mRNA dose that would result in production of 150U-300U HYAL. One would have been motivated to do so with a reasonable expectation of success because effective doses were known and because WO196 teaches determining a dose to administer their mRNA-encapsulating LNPs is a routine matter for an artisan and that artisans use various known criteria to determine a dose for a subject. Therefore the instant claims would have been obvious in view of the patented claims and the teachings of WO196, WO917, Webb, Turner, Kuhn, WO774, Weissman, and Grissinger, US638, Pardi, and Hylenex, and using the instant methods would require the composition/methods of the patented claims.
Claims 1, 6-7, 10, 12-14, 18-19, 22-24, 27, and 37 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 WO196, WO917, Webb, Turner, Kuhn, Weissman, WO774, Grissinger, US638, Pardi, and Hylenex.
The provisional rejection over App. No. 19/029962 has converted to a nonprovisional rejection since the invention has issued as US Patent No. 12459885. The basis for the rejection is the same and updated in response to the claim amendments. Claims 1, 6-7, 10, 12-14, 18-19, 22-24, 27, and 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-19 of US Patent No. 12459885 in view of WO196, WO917, Webb, Turner, Kuhn, Weissman, WO774, Grissinger, US638, Pardi, and Hylenex.
NOTE: page # references in WO documents refer to the PDF page #.
All references besides Grissinger, US638, Pardi, and Hylenex are of record. 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
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
18/890983
US20250145577
All besides canceled
18/910694
US20250049954
82-86
19/027390
All besides canceled
19/027437
All besides canceled
19/233547
All besides canceled
19/029962
now issued as US Patent No. 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 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 WO196, WO917, and Weissman. Briefly, WO196 teaches (¶86) administering more than one polynt and (¶129) subcutaneous administration; WO917 teaches (p. 70 L22-25) mammalian HYAL are endo-β-N-acetyl-hexosaminidases, (pp. 6-7 L10-5) administering the HYAL agent and the second agent sequentially and at different timepoints in relation to one another and (p. 155 §3. Use as a spreading agent and p. 158 §6. Gene therapy applications) HYAL facilitates drug delivery including viral gene therapies; Webb teaches (§Comment ¶1-3) subcutaneously injecting a HYAL improves uptake by the circulatory system of fluids and drugs; Turner teaches (§Abstract) subcutaneous administration of drugs is cost effective and convenient and (§Immunogenicity considerations) protein therapeutics can be immunogenic; Kuhn teaches (§mRNA-based gene therapy) mRNA therapeutic can be designed to have reduced immunogenicity; and Weissman teaches (§Protein replacement therapies) the benefits of using mRNA to express a protein instead of using manufactured protein (which is expensive) or (§Introduction ¶2) a virus (because a virus can integrate into the genome and cause mutagenesis, which is not a risk of administering mRNA). Additionally, the other claim limitations are taught as follows: syringe (Grissinger, §Safe Practice Recommendations ¶2-3) and dosing (US638, Table 19, starts after ¶279; ¶238-239, Fig. 5; Pardi, §Abstract; and Hylenex, §Dosage and Administration).
WO774 teaches (p. 25 L15-20) SEQ ID NO 190, which encodes a bovine HYAL that comprises 100% identity to claimed SEQ ID NO 10, and an AA sequence for bovine HYAL comprising 100% sequence identity to claimed SEQ ID NO 11. Those alignments are shown 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 of WO196, WO917, Webb, Turner, Kuhn, and Weissman, and sequences of WO774, 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 Grissinger, US638, Pardi, and Hylenex, for benefits of using one needle and one syringe only one time is a standard practice in healthcare, administering mRNA encapsulating LNP at doses that are routine and conventional in the art, and administering the blended LNP formulation comprising HYAL encoding mRNA at an mRNA dose that would result in production of 150U-300U HYAL. One would have been motivated to do so with a reasonable expectation of success because effective doses were known and because WO196 teaches determining a dose to administer their mRNA-encapsulating LNPs is a routine matter for an artisan and that artisans use various known criteria to determine a dose for a subject. Therefore the instant claims would have been obvious in view of the copending claims and the teachings of WO196, WO917, Webb, Turner, Kuhn, WO774, Weissman, and Grissinger, US638, Pardi, and Hylenex, 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, and 37 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 WO196, WO917, Webb, Turner, Kuhn, Weissman, WO774, Grissinger, US638, Pardi, and Hylenex. NOTE: page # references in WO documents refer to the PDF page #. All references besides Grissinger, US638, Pardi, and Hylenex are of record. 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/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 WO196, WO917, and Weissman. Briefly, WO196 teaches (¶86) administering more than one polynt and (¶129) subcutaneous administration; WO917 teaches (p. 70 L22-25) mammalian HYAL are endo-β-N-acetyl-hexosaminidases, (pp. 6-7 L10-5) administering the HYAL agent and the second agent sequentially and at different timepoints in relation to one another and (p. 155 §3. Use as a spreading agent and p. 158 §6. Gene therapy applications) HYAL facilitates drug delivery including viral gene therapies; Webb teaches (§Comment ¶1-3) subcutaneously injecting a HYAL improves uptake by the circulatory system of fluids and drugs; Turner teaches (§Abstract) subcutaneous administration of drugs is cost effective and convenient and (§Immunogenicity considerations) protein therapeutics can be immunogenic; Kuhn teaches (§mRNA-based gene therapy) mRNA therapeutic can be designed to have reduced immunogenicity; and Weissman teaches (§Protein replacement therapies) the benefits of using mRNA to express a protein instead of using manufactured protein (which is expensive) or (§Introduction ¶2) a virus (because a virus can integrate into the genome and cause mutagenesis, which is not a risk of administering mRNA). Additionally, the other claim limitations are taught as follows: syringe (Grissinger, §Safe Practice Recommendations ¶2-3) and dosing (US638, Table 19, starts after ¶279; ¶238-239, Fig. 5; Pardi, §Abstract; and Hylenex, §Dosage and Administration).
WO774 teaches (p. 25 L15-20) SEQ ID NO 190, which encodes a bovine HYAL that comprises 100% identity to claimed SEQ ID NO 10, and an AA sequence for bovine HYAL comprising 100% sequence identity to claimed SEQ ID NO 11. Those alignments are shown above.
Therefore it would have been obvious to an artisan before the effective filing date of the instant invention to modify the patented/copending claims with the teachings of WO196, WO917, Webb, Turner, Kuhn, and Weissman, and sequences of WO774, 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 Grissinger, US638, Pardi, and Hylenex, for benefits of using one needle and one syringe only one time is a standard practice in healthcare, administering mRNA encapsulating LNP at doses that are routine and conventional in the art, and administering the blended LNP formulation comprising HYAL encoding mRNA at an mRNA dose that would result in production of 150U-300U HYAL. One would have been motivated to do so with a reasonable expectation of success because effective doses were known and because WO196 teaches determining a dose to administer their mRNA-encapsulating LNPs is a routine matter for an artisan and that artisans use various known criteria to determine a dose for a subject. Therefore the instant claims would have been obvious in view of the patented/copending claims and the teachings of WO196, WO917, Webb, Turner, Kuhn, WO774, Weissman, and Grissinger, US638, Pardi, and Hylenex, and using the instant methods would require the composition/methods of the patented/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, and 37 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 WO196, WO917, Webb, Turner, Kuhn, Weissman, WO774, Grissinger, US638, Pardi, and Hylenex. NOTE: page # references in WO documents refer to the PDF page #. All references besides Grissinger, US638, Pardi, and Hylenex are of record. 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
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. All claims sets are broadly directed to mRNAs encoding therapeutic proteins or that encode OTC.
The patented/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 WO196, WO917, and Weissman. Briefly, WO196 teaches (¶86) administering more than one polynt and (¶129) subcutaneous administration; WO917 teaches (p. 70 L22-25) mammalian HYAL are endo-β-N-acetyl-hexosaminidases, (pp. 6-7 L10-5) administering the HYAL agent and the second agent sequentially and at different timepoints in relation to one another and that (p. 155 §3. Use as a spreading agent and p. 158 §6. Gene therapy applications) HYAL facilitates drug delivery including viral gene therapies; Webb teaches (§Comment ¶1-3) subcutaneously injecting a HYAL improves uptake by the circulatory system of fluids and drugs; Turner teaches (§Abstract) subcutaneous administration of drugs is cost effective and convenient and (§Immunogenicity considerations) protein therapeutics can be immunogenic; Kuhn teaches (§mRNA-based gene therapy) mRNA therapeutic can be designed to have reduced immunogenicity; and Weissman teaches (§Protein replacement therapies) the benefits of using mRNA to express a protein instead of using manufactured protein (which is expensive) or (§Introduction ¶2) a virus (because a virus can integrate into the genome and cause mutagenesis, which is not a risk of administering mRNA). Additionally, the other claim limitations are taught as follows: syringe (Grissinger, §Safe Practice Recommendations ¶2-3) and dosing (US638, Table 19, starts after ¶279; ¶238-239, Fig. 5; Pardi, §Abstract; and Hylenex, §Dosage and Administration).
WO774 teaches (p. 25 L15-20) SEQ ID NO 190, which encodes a bovine HYAL that comprises 100% identity to claimed SEQ ID NO 10, and an AA sequence for bovine HYAL comprising 100% sequence identity to claimed SEQ ID NO 11. Those alignments are shown 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 of WO196, WO917, Webb, Turner, Kuhn, and Weissman, and sequences of WO774, 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 Grissinger, US638, Pardi, and Hylenex, for benefits of using one needle and one syringe only one time is a standard practice in healthcare, administering mRNA encapsulating LNP at doses that are routine and conventional in the art, and administering the blended LNP formulation comprising HYAL encoding mRNA at an mRNA dose that would result in production of 150U-300U HYAL. One would have been motivated to do so with a reasonable expectation of success because effective doses were known and because WO196 teaches determining a dose to administer their mRNA-encapsulating LNPs is a routine matter for an artisan and that artisans use various known criteria to determine a dose for a subject. Therefore the instant claims would have been obvious in view of the patented or copending claims and the teachings of WO196, WO917, Webb, Turner, Kuhn, WO774, and Weissman, and Grissinger, US638, Pardi, and Hylenex, and using the instant methods would require the composition/methods of the patented/copending claims. The patented/copending mRNAs or therapeutic mRNAs 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 08 December 2025 have been fully considered but they are not persuasive. Each rejection is addressed below. Arguments that are no longer relevant are not addressed.
Objections
Claims 1 and 23 are objected to for minor informalities.
112b
A new rejection has been applied because Claim 24 is unclear.
112d
A new rejection has been applied because Claim 22 doesn’t limit the scope of Claim 1.
103
Applicant argues against the 103 rejections on pp. 7-10. Applicant argues that WO196 doesn’t teach the features of Claim 1. Applicant argues that WO196 discloses a blend of LNPs and therefore cannot be used to teach administration of separate LNPs. Applicant argues that separate administration would have rendered the blended LNP formulation unsatisfactory for its intended purpose.
Those arguments are not persuasive because they hinge on a misunderstanding of what WO196 considers blended LNPs. As discussed in the 103 rejection, WO196’s “blend” of LNPs refers to a lipid blend, not a blend of LNPs wherein each LNP encapsulates a different mRNA. Indeed, WO196’s ¶5 that Applicant points to in their arguments states …this unexpected discovery of synergistic enhancement between different lipid formulations has significant implication in messenger RNA therapy… [emphasis added]. That § also states that the synergistic effect is not nucleic acid specific.
As discussed in the 103 rejection, WO196 teaches that (¶7) blended LNPs refers to blended lipid—not blended polynt—formulations:
As used herein, the term “blend”, “blended”, or grammatical equivalent, refers to a combination of two or more separate, non-identical formulations. Typically, the two or more separate, non-identical formulations are combined or blended into one composition, such as, a suspension, as depicted, for example, in FIG. 1. As used herein, non-identical formulations refer to formulations containing at least one distinct lipid component. In some embodiments, non-identical formulations suitable for blend contain at least one distinct cationic lipid component. The term “blend” as used herein is distinguishable from the terms “mix” or “mixture”, which are used herein to define a single formulation containing multiple non-identical cationic/ionizable lipids, multiple non-identical helper lipids, and/or multiple nonidentical PEGylated lipids. In some embodiments, a “mix” formulation contains at least two or more non-identical cationic/ionizable lipids. Typically, a “mix” formulation contains a single homogeneous population of lipid nanoparticles. [emphasis added.]
WO196 further clarifies that it is the blend of lipids that (¶5) synergistically enhances mRNA expression because the blend of LNP can comprise only a single polynt. WO196 teaches it is the blend of LNPs—not the blend of polynt or simultaneous administration of polynt—that increases mRNA expression. Descriptions at ¶9-15 and subsequent passages indicate that WO196’s invention is synergistic enhancement of enhancement due to different lipid formulations—not among two or more polynt delivered together. To that point, WO196 teaches (¶9):
In certain embodiments, the blended first lipid nanoparticle and second lipid nanoparticle comprise the same one or more polynucleotides, wherein the expression of the one or more polynucleotides by the target cells following the administration (e.g., intravenously) of the blended pharmaceutical composition to a subject exceeds the relative sum of the expression of the one or more polynucleotides achieved by the first lipid nanoparticle and the expression of the one or more polynucleotides achieved by the second lipid nanoparticle when the first lipid nanoparticle and the second lipid nanoparticle are administered to the subject independently of each other. [emphasis added.]
WO196 continues (¶11), teaching that the blend of LNPs enhances expression of even a single polynt compared to when the polynt is delivered with a nonblended LNP:
In another embodiment, only one of the two or more lipid nanoparticles that comprise the blended composition comprises or encapsulates a polynucleotide. For example, where the pharmaceutical compositions comprises two blended lipid nanoparticles, only the first lipid nanoparticle comprises one or more polynucleotides while the second lipid nanoparticle does not comprise a polynucleotide (i.e., the second polynucleotide [sic] is empty). In such an embodiment, following the administration (e.g., intravenously) of the two blended first and second lipid nanoparticles that comprise the pharmaceutical composition to the subject, the production of one or more polypeptides or proteins encoded by the encapsulated polynucleotides by a target cell is enhanced relative to the production of one or more polypeptides or proteins observed when the first lipid nanoparticle is administered to the subject independently of the second lipid nanoparticle. [emphasis added.]
That indicates that expression of even a single is enhanced when lipid-blend LNPs are administered. WO196 continues (¶12-15) the same explanation: it is the blend of LNPs that results in unexpectedly improve expression of mRNA. WO196 teaches (¶37) their “blend” or “blended” formulation comprises two or more different [LNPs] whereas a “mix” or “mixture” describes a pharmaceutical formulation or composition that includes only a single lipid nanoparticle in the formulation… the terms mix and mixture… refer to a pharmaceutical composition comprising only a single population of [LNP], [which] have the same or substantially the same lipid composition.
All of those teachings indicate that WO196 teaches their blend of LNPs can comprise only a single polynt, and merely administering the polynt within a lipid-blend of LNPs enhances expression. Therefore Applicant’s argument that (p. 9 ¶3)
WO917 cannot cure WO196's deficiencies at least because any modification to WO196's blended LNP formulation to separately formulate/administer the first and second (or more) LNPs would have rendered the blended LNP formulation unsatisfactory for its intended purpose and otherwise changed its principle of operation
is not persuasive since it relies on the misunderstanding that WO196’s blended LNPs are a blend of an LNP encapsulating one mRNA and a second LNP encapsulating a second mRNA. As discussed in detail, WO196’s blended LNPs refer to a lipid blend and they can be used to administer a single mRNA whose expression WO196 teaches will be higher than if the single mRNA is administered in a non-lipid blended LNP. The instant claims recite open language of a first formulation [that] comprises a first LNP and a second formulation [that] comprises a second LNP. Nothing in the instant claims prohibits lipid-blended LNP. As discussed, WO196 allows for a lipid blended LNP wherein only one member of the LNP blend encapsulates an mRNA and wherein the other member of the LNP blend is empty.
Furthermore, as discussed in the rejection, the other references teach benefits of administering mRNA instead of protein and Webb and WO917 teach that HYAL breaks down the ECM to improve uptake of a drug. Although WO917 teaches administering a HYAL enzyme and not an mRNA encoding HYAL, the references of Kuhn and Weissman describe cost-saving and immunological benefits of administering mRNA rather than enzyme. Therefore it would have been obvious to a person of ordinary skill in the art to administer an LNP encapsulating an mRNA encoding HYAL so the HYAL is expressed and breaks down the ECM, and to then, later, administer another LNP encapsulating an mRNA encoding any protein.
A person of ordinary skill is a person of ordinary creativity and all the elements of the claimed invention were of known benefits.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
In addition to the factors above, Office personnel may rely on their own technical expertise to describe the knowledge and skills of a person of ordinary skill in the art. The Federal Circuit has stated that examiners and administrative patent judges on the Board are "persons of scientific competence in the fields in which they work" and that their findings are "informed by their scientific knowledge, as to the meaning of prior art references to persons of ordinary skill in the art." In re Berg, 320 F.3d 1310, 1315, 65 USPQ2d 2003, 2007 (Fed. Cir. 2003). In addition, examiners "are assumed to have some expertise in interpreting the references and to be familiar from their work with the level of skill in the art ." PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 86 USPQ2d 1385 (Fed. Cir. 2008) (quoting Am. Hoist & Derrick Co. v. Sowa & Sons, 725 F.2d 1350, 1360, 220 USPQ 763, 770 (Fed. Cir. 1984). See MPEP § 2141.03 for a discussion of the level of ordinary skill.
MPEP §2141(II)(c)
Applicant’s other arguments are not persuasive because the arguments against WO196 in view of the other references are not persuasive.
NSDP
Applicant makes the same arguments against the NSDP rejections. Those arguments aren’t persuasive because WO196 and the other references would have made obvious administering a first formulation comprising an LNP encapsulating a HYAL mRNA to break down the ECM and then, later, a second LNP encapsulating any other mRNA. As discussed, using HYAL to break down the ECM and improve uptake of a drug was well known in the art. It was also well known to administer mRNA encoding a protein rather than the protein itself, and doing so was known to provide cost-savings and immunological benefits as taught by Kuhn and Weissman. It would have been obvious to use the method that would have been obvious in view of _______ to administer any mRNA for the benefit of enhancing uptake of a “nonhelper mRNA”. The nonhelper mRNA can be any mRNA so the broad instant claims would have been obvious over any patented or copending application that claims any mRNA, in view of the prior art. The prior art teaches why it is beneficial to administer HYAL before administering another drug, why mRNA encoding a protein is preferable to administering the protein itself, 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 has not provided any clear explanation how these inventions aren’t obvious over each other.
As discussed in the response to arguments against the 103 rejections, the claimed method of subcutaneously administering an mRNA encoding a HYAL that degrades the ECM and improves exposure of a subject’s circulatory system to the subcutaneous tissue and injecting any mRNA would have been obvious because all of the elements of the claimed invention were known: WO196 (and other references as cited) teaches mRNA that encodes a HYAL enzyme. Webb teaches subcutaneously administering HYAL protein degrades the ECM and thereby improves uptake of subcutaneous fluids and drugs by a subject’s circulatory system. Turner teaches benefits of subcutaneous administration of drugs. Weismann and Kuhn teach benefits of administering mRNA rather than protein and, together with teachings in Turner, reasons to administer a protein drug as mRNA. Then the other references teach all the other claim elements. The teachings of WO196, Webb, Turner, Kuhn, and Weismann would have made it obvious to administer an LNP encapsulating an mRNA encoding a HYAL enzyme before or in conjunction with an LNP encapsulating any mRNA of interest because of Webb’s teachings that HYAL degrades the ECM and improves uptake of a drug. Injecting an mRNA encoding a HYAL—rather than HYAL protein itself—would have been obvious because Kuhn and Weismann teach benefits of administering mRNA instead of protein (i.e., lower cost, less immunogenic) and at least one of those benefits addresses a difficulty of protein therapeutics taught by Turner (i.e., immunogenicity and antidrug antibodies).
An artisan would have put those teachings together and decided to administer LNPs comprising a hyaluronidase mRNA for the cost and immunogenicity benefits taught by Kuhn and Weissman; doing so would have broken down the ECM as taught by Webb and WO917. An artisan would have then administered the mRNA encoding OTC—or any mRNA—and would have expected better delivery because that is what Webb and WO917 teach will occur after degrading the ECM with HYAL. An artisan would have wanted to improve delivery of any of the patented or copending therapeutic mRNAs so they would have used the instantly claimed methods with any of the patented or copending therapeutic mRNAs. Therefore the NSDP rejections must be maintained.
Conclusion
Claims 1, 6-7, 10, 12-14, 18-19, 22-24, 27, and 37 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUTHIE S ARIETI whose telephone number is (571)272-1293. The examiner can normally be reached M-Th 8:30AM-4PM, alternate Fridays 8:30AM-4PM (ET).
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RUTHIE S ARIETI
Examiner (Ruth.Arieti@uspto.gov)
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636