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 .
Status of Claims
Claims 1-20 are pending and are being examined.
Priority
Claims 1-20 are a CON of PCT/EP 2021/053370 filed on February 11, 2021, which claims priority to EP 21156423.2 filed on February 10, 2021, and to EP 20156987.8 filed on February 12, 2020, and to EP 20000064.4 filed on February 2/11/2020.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on August 10, 2022, and on March 6, 2025, was filed before the mailing of the First Office Action on August 23, 2025. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Objection to Abstract
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps. Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length. As currently presented, the abstract is no in narrative form and essentially restates the language of claim 1 rather than providing a concise summary of the invention disclosed. Additionally, Applicant is reminded that it is preferable that the abstract be within the range of 50 to 150 words.
Claim Objections
Claim 19 is objected to because of the following informalities: Claim 19 recites “…administering to a subject suffering from the disease and effective amount of a construct according to claim 1” should read “…from the disease an effective amount…”.
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.
Claims 1, 2, 5, 6, 7, 8, 12, 13, 14, 15, 16, 17, and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 24 of copending Application No. 17/173,109 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Claim 1 of the instant application recites a recombinant nucleic acid construct comprising 5’ UTR selected from MCP-1 and 3’ UTR selected from vWF. Claim 1 of the reference application, 17/173,109, also recites a recombinant nucleic acid construct in the 5’ to 3’ direction that includes a 5’ UTR encoding MCP-1 and a 3’ UTR encoding vWF, wherein the effector molecule is effective at restoring a cellular function of a cell, and wherein the recombinant nucleic acid construct differs from the wild-type mRNA encoding the effector molecule. Both claims are directed to the same specified UTRs, i.e. 5’ MCP-1 and 3’ vWF UTR regions, and both claims are directed at the same purpose of expressing an effector molecule to restore cellular function.
In Claim 1, the effector molecule of the instant application encompasses any mutant effector molecule that exhibits a gain-of-function or hypermorphic effect which is functionally equivalent to the “hyperactive Tie-2 R849W” listed in the Markush grouping of Claim 24 depending on Claim 21 in Application 17/173,109. The hyperactive mutation in Tie-2, i.e. R849W, is representative of a gain-of-function species claimed in the reference application because the gain-of-function mutant effector molecule enhances normal activity of the protein. This falls within the definition of both “gain-of-function” and “hypermorphic” as recited in Claim 1 of the instant application. Because of this, Claim 1’s language broadly covers the genus of the previously claimed species without introducing any additional functional or structural differences.
Claim 2 of the instant application recites “the recombinant nucleic acid construct of claim 1, wherein the mutant effector molecule is a mutant Tie-2 and wherein the mutant Tie-2 optionally is selected from the group comprising…Tie-2 R849W…”. In US Application 17/173,109, Claim 21 recites a method for expressing an effector molecule in an endothelial cell, comprising delivering a recombinant nucleic acid construct according to claim 1 to said endothelial cell. Additionally, Claim 24 recites: “the method according to claim 21, wherein said effector molecule is selected from the group consisting of…hyperactive Tie-2 receptor R849W”. Under the broadest reasonable interpretation, the term “hyperactive Tie-2 receptor R849W” of claim 24 can encompass the “mutant Tie-2 R849W” recited in claim 2 of the instant application. The teachings of claim 21 in Application 17/173,109 further demonstrate that the method expressly encompasses the expression of hyperactive mutants, including Tie-2 R849W, in endothelial cells. Based on this, Claim 2 of the instant application is not patentably distinct from the combination of Claims 21 and 24 of Application 17/173,109 particularly with respect to the Tie-2 R849W mutant.
Claim 5 of the instant application recites a recombinant nucleic acid construct comprising 5’ UTR selected from MCP-1 and 3’ UTR selected from vWF. Claim 1 of the reference application, 17/173,109, also recites a recombinant nucleic acid construct in the 5’ to 3’ direction that includes a 5’ UTR encoding MCP-1 and a 3’ UTR encoding vWF. Because of this, there are no non-obvious functional distinctions between the construct in Claim 5 of the instant applicant and the construct of Claim 1 of the reference application.
Claim 6 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/173,109 in view of Bennett [RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform, Annu. Rev. Pharmacol. Toxicol., 2010]. Claim 6 is directed to an antisense construct in the 3’ to 5’ direction where the 3’ UTR is vWF and the 5’ location is a MCP-1 UTR. This would be an obvious variation on orientation as it is the antisense of the recombinant nucleic acid construct of Claim 1 in the reference application where the nucleic acid construct is 5’ to 3’ with the 5’ UTR being MCP-1 and the 3’ UTR being vWF. As stated in Bennet, antisense nucleotides are not a new concept as a therapeutic platform [Introduction: an RNA world ¶ 4 pg. 261]. Bennett further states antisense nucleotides are designed to bind to the target RNA by well characterized Watson-Crick base pairing, and once bound, are capable of modulating its function through a variety of post-binding events [Abstract]. The 3’ to 5’ orientation is recognized as a valid configuration for antisense constructs.
Claim 7 of the instant application recites a recombinant nucleic acid construct comprising 5’ UTR selected from MCP-1 and 3’ UTR selected from vWF. Claim 1 of the reference application, 17/173,109, also recites a recombinant nucleic acid construct in the 5’ to 3’ direction that includes a 5’ UTR encoding MCP-1 and a 3’ UTR encoding vWF. Because of this, there are no non-obvious functional distinctions between the construct in Claim 5 of the instant applicant and the construct of Claim 1 of the reference application.
Claim 8 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 7 of copending Application No. 17/173,109 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both claims recite a recombinant nucleic acid construct comprising a poly-A tail, and the additional limitation in claim 8, i.e. the poly-A tail is optionally at the 3’ terminal end, would have been routine and predictable to a person ordinary skill in the art.
Claim 12 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 10 of copending Application No. 17/173,109 (reference application). Claim 12, which depends from Claim 11, recites a construct comprising a signal peptide within the construct that includes the same series of signal peptides, i.e. MCP-1, IL-6, Ang-2, and Ang-1. Although claim 12 of the instant application depends from a base claim that does not explicitly recite a poly-A tail, the additional features of nucleotide sequences coding for the signal peptides are identical to those recited in claim 12 of the reference application.
Claims 13 and 14 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 and 14 of copending Application No. 17/173,109 (reference application). Claims 13 and 14, both of which depend from Claim 1, are not patentably distinct. Both applications recite a recombinant nucleic acid construct used to restore cellular function or to exert a therapeutic effect. The only difference in claim 13 of the instant application is the additional “optional” language where the endothelial cell is a vascular endothelial cell. However, this does not create a meaningful functional or structural limitation. Similarly, Claim 14 of both applications, which both depend from Claim 1 of the respective applications, recite restoration occurs through multiple pathways including Tie-2 signaling pathway, VEGF signaling pathway, NOTCH signaling pathway, etc. Because of this, the functional outcomes are the same.
Claims 15, 16, and 17 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15, 16, and 17 of copending Application No. 17/173,109 (reference application). Claim 15 of both applications recites a vector comprising the nucleic acid construct of claim 1, and Claim 16 of both applications recites a cell comprising the nucleic acid construct of claim 1. Claim 17 of both applications recites a delivery vehicle containing the nucleic acid construct where the delivery vehicle is a cationic lipid particle where optionally the particle is a nanoparticle between the sizes of 30 nm to 200 nm. The claims of the instant application and the reference application are structurally and functionally identical.
Claim 18 is provisionally rejected on the ground of nonstatutatory double patenting as being unpatentable over claim 18 of copending Application No. 17/173,109 (reference application). Claim 18 of the instant application is directed to a pharmaceutical composition comprising the nucleic acid construct of claim 1 along with a pharmaceutically acceptable diluent. The composition recited in the instant claim is identical in structure and function to the composition recited in the reference claim with no readily discernable differences.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 19 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention:
The nature of the invention:
The nature of the invention is directed to a recombinant nucleic acid construct with selected 5’ and 3’ untranslated regions used in treating or preventing disease.
The breadth of the claims:
Specifically, the claims are broad, drawn to treating or preventing a disease, in any subject, and restoring function of any cell, by administering to any cells of the subject, or to any cell, the recombinant nucleic acid construct of Claim 1, i.e. a recombinant nucleic acid construct comprising a 5’, coding region of an effector molecule, and a 3’ UTR.
The amount of direction or guidance present in the Application:
Applicant’s specification discusses the structure of the mRNA being a 5’ UTR coding region with a 3’ UTR coding region followed by a Markush of both 5’ UTRs and 3’ UTRs [¶ 008]. With the specification only providing several examples of a coding sequence being effective for increased protein expression, the specification primarily teaches general intent to treat and/or prevent disease and to restore cellular function of any cell [¶ 0023].
Applicant’s specification goes on to state a pharmaceutical composition comprising the recombinant nucleic acid construct is used for treating and/or preventing disease [¶ 001]. The specification further states the administered mRNA sequence “can cause a cell to make a protein, which in turn could directly treat a disease or could function as a vaccine” [¶ 004]. It could also act in a way where a protein could interfere with an element of a pathway resulting in inhibition or stimulation thereby ameliorating a disease [Id.]. The specification further states in an embodiment, the nucleic acid construct could be used to restore cellular function, encompass killing of a cell, killing a tumor endothelial cell, or an embodiment could restore cellular function as it relates to neo angiogenesis in reference to vascular disease [¶ 0022]. The specification then describes an embodiment of the first through fifth aspect to include treating a disease characterized by vascular leakage, and more specifically vascular leakage and micro vascular leakage of endothelial cells [¶ 0076]. The specification goes onto to list diseases such as acute respiratory distress syndrome, pneumonia, sepsis, trauma, bacteremia, endotoxemia, burns, etc [¶ 0077-0085]. The specification also lists other diseases such as malaria, Clarkson disease, dengue virus infection, leakage associated infections, vascular malformation, and even rheumatoid arthritis and liver fibrosis [¶ 00213]. Aside from this, the specification only provides high-level statements about targeting endothelial cells and possible signaling effects with no mention as to how the claimed invention would treat the multitude of listed diseases or provide examples in vitro or in animal models. Furthermore, Applicant’s specification lacks detailed protocols for any specific disease other than generically listing a type of disease such certain types of pneumonia or cancer [¶ 00213]. The specification goes on to also state that the mutant an effector molecule could also be used in reparative regeneration citing mutant effector molecules are useful in the treatment of Alzheimer’s disease, but again, this statement seems to only be conclusory [¶ 00215]. Additionally, the specification the cellular function restoration by an effector molecule is directed only towards an endothelial cell [¶ 0021]. For example, the specification lists that the effector molecule will have an anti-permeability effect, an anti-vascular leakage effect, an apoptotic effect, anti-inflammatory effect, or an anti-stress response effect on endothelial cells [Id.]. In the same paragraph, the specification lists various pathways associated with these effects such as Tie-2 signaling pathway, VEGF pathway, and NOTCH signaling pathway to name a few.
In all, the Applicant’s specification only provides a generic level of detail where the treating and/or preventing of a disease appears to be more conclusory than substantiated.
The presence or absence of working examples:
The specification limits the number of working examples to only a few. At paragraph [00550], Applicant’s specification lists expression of luciferase using Ang-1 or Ang-1 derivatives expressing the recombinant nucleic acid constructs in HPMEC, HUVEC, HPAEC, and HeLa cells. The specification further states that HPMEC cells were chosen given these cells are the most appropriate for studying human lung diseases [¶ 00552]. mRNA transfection was carried out using Lipofectamin MessengerMAX and can be successfully monitored using known methods such as Green Fluorescent Protein (GFP) [¶ 00554]. In example 3, modified mRNAs encoding the activating Tie-2 mutations, e.g. R849W were transfected into different cell lines such as HeLa and primary endothelial cells such as HUVECs or HPMECs. This was done in conjunction with mRNAs encoding the wild-type Tie-2 using Lipofectamin MessengerMAX [¶ 00568]. The Tie-2 mutation transfected cells were then analyzed against the wild-type Tie-2 and to non-transfected cells where the mutated Tie-2 was better at activating the Tie-2 signaling pathway compared to the wild-type Tie-2 encoding mRNAs [Id.]. The next example are mRNA lipid nanoparticles where the same procedure used for siRNAs could be utilized where the formulations were tested for particle size [¶ 00575]. Additional examples are similar in that only mammalian cell cultures are used where these cells are transfected and then analyzed for the requisite expression. Lastly, the examples provided by Applicant appear to be geared more towards proof-of-concept as opposed to applied research.
The relative skill of those in the art:
A person of ordinary skill in the art in this field at the time of invention would likely have a graduate level education along with several years of experience with gene expression systems, recombinant nucleic acid design, and endothelial cell signaling pathways. The Artisan would also have experience with cloning, expression analysis, and cell culture models of vascular endothelium. Given this, the level of ordinary skill in the art for creating a recombinant nucleic acid construct for treating and preventing a disease in a subject is high, as an ordinary artisan in this art needs specialized knowledge of the complex nature of recombinant nucleic acid design as well as methods for transfecting such recombinant nucleic acids.
Predictability or lack thereof in the art:
The development of recombinant nucleic acid constructs and their applications in gene therapy are an active area of research. Furthermore, while general gene delivery strategies have existed, these strategies do not provide or establish a predictable outcome. This is true even for therapeutic gene delivery systems designed for targeting endothelial cells. For example, an article by the Johns Hopkins Institute for Nanobiotechnology recognized that success with mRNA-based therapeutics require precise control of expression, stability, and delivery. The article emphasized that optimizing untranslated regions require extensive testing to achieve desired protein expression in the relevant cell [The disease-fighting promise of mRNA, 2025]. The article further states that broad application to more systemic diseases with complex signaling pathways require more significant advancements, and to date, were not available. Additionally, Wu et al., discussing targeting polygenic or multifactorial conditions such as cardiovascular disease, involve substantial challenges due to genetic heterogeneity and environmental modifiers [Gene therapy for polygenic or complex disease, Biomarker Research, 2024, ¶ 1]. Wu et al. further discusses that diseases such as heart disease or Alzheimer’s disease are influenced by a variation of multiple genes. The role of epigenetics in cardiovascular diseases have recently been demonstrated. These mechanisms include such things as DNA methylation, histone modification, and non-coding RNA. All of these regulate genes associated with the disease pathology. Although there are treatments currently in clinical trials, these trials involve the use of cDNA [Coronary heart disease, ¶ 1]. Applicant’s own specification states there is a level of unpredictability with respect to distinct protein expression activity in different cell types [¶ 00565]. Combined, the state of the art demonstrates that despite nucleic acid engineering having been well studied, the predictability of achieving for treating and/or preventing a disease even in the context of achieving anti-vascular leakage or anti-apoptotic effects across diverse diseases is low. There are no standardized accepted protocols for ensuring the inclusion of particular UTRs, along with other elements forming the recombinant nucleic acid, will result in a therapeutic effect.
The quantify of experimentation needed:
The specification lacks protocols other than general transfection methods used in standard research protocols. Given this and Applicant’s own admission that protein expression is construct dependent and cell-type dependent, a person of ordinary skill would need to conduct extensive experimentation where they design constructs, test delivery methods, and perform disease specific studies and the ongoing research in this field of endeavor, an Artisan would have to engage in undue experimentation.
Conclusion:
Given the above reasons, Claims 19 and 20 are not enabled for other than a method of expressing an mRNA in an endothelial cell. Applicant being directed to the expression levels found in endothelial cells, and lack of specific discussion regarding any specific gene and/or disease, and to nucleic acid construct can be utilized in a therapeutic manner on a subject, the specification leaves it to a person of ordinary skill in the art to reconcile or account for current state of the art.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 are 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.
Claim 1 uses the generic phrase “a derivative thereof having a nucleotide identity of at least 85%” as it relates to 5’ and 3’ untranslated region of the listed genes being incorporated into a recombinant nucleic acid construct. The same generic scope of “a derivative thereof having a nucleotide identity of at least 85%” is present in each of the dependent claims, i.e. Claims 2-4, 8-20.
Claim 5 uses the generic phrase “a derivative thereof having a nucleotide identity of at least 85%” as it relates to 5’ and 3’ untranslated region of the listed genes being incorporated into a recombinant nucleic acid construct.
Claim 6 uses the generic phrase “a derivative thereof having a nucleotide identity of at least 85%” as it relates to 5’ and 3’ untranslated region of the listed genes being incorporated into a recombinant nucleic acid construct.
Claim 7 uses the generic phrase “a derivative thereof having a nucleotide identity of at least 85%” as it relates to 5’ and 3’ untranslated region of the listed genes being incorporated into a recombinant nucleic acid construct.
The specification provides antecedent basis for “a derivative thereof having a nucleotide identity of at least 85%” in relation to the 5’ and 3’ untranslated regions of the listed genes [¶ 008].
Applicant’s specification states numerous times in relation to the 5’ or 3’ untranslated regions of the cited genes can include aside from the whole untranslated region “a derivative thereof having a nucleotide identity of at least 85%” can be used in place of the whole untranslated region [¶ 008]. This is repeated throughout the Applicant’s specification referencing both 5’ and 3’ regions of such genes as MCP-1, Ang-2 HSP70, H3.3, Galectin-9, GADD34, and several other genes where either the 5’ or 3’ untranslated region of the gene is incorporated into a recombinant nucleic acid sequence construct [¶ 008, 0011, 00163, 00182]. However, the specification does not disclose any construct containing a derivative sequence as claimed. It also does not provide any representative examples or other identifying characteristics such as conserved motif descriptions. Applicant’s drawings also do not disclose any construct containing a derivative sequence as claimed. The specification also does not disclose any representative species of a recombinant nucleic acid construct containing derivatives of the untranslated regions within the claimed percent identity range. Citing MPEP 2163 II part A3(a)(ii), a court in Ariad Pharm., Inc. v. Eli Lilly & Co. stated "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted)" [598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)]. For example, Garcia et al. demonstrate that heterogeneity in 5’ UTR sequence characteristics can impact translation efficiency. The authors noted that upstream ‘AUGs’ were found to repress translation to varying degrees, depending on their position and context, while combinations of upstream ‘AUGs’ had a non-additive effect [Functional characterization of 5’ UTR cis-acting sequence elements that modulate translational efficiency in Plasmodium falciparum and humans, Malaria Journal, 2022, Results ¶ 2]. Garcia et al. also discloses that the base composition, e.g. GC content within the 5’ UTR modulates translation efficiency in a lesser extent than upstream start codons showing that truncated or modified versions of wild-type ‘UTR can meaningfully alter translational dynamics relative to the wild-type UTR [Id.]. In addition to Garcia et al., Olandini von Niessen et al. teaches that even partial UTR fragments, as when only the central region is used, e.g. nucleotide 37-107, result in a measurable drop in stability and expression compared to the full-length UTR [US 2019/0071682 A1, Publication 2019, ¶ 0427-0428]. Because of this, a person of ordinary skill would not be able to determine, based on the specification, which specific nucleotides within the recited untranslated region sequences could be deleted, substituted, or otherwise modified to yield a sequence derivative with at least 85% identity while retaining the relevant and/or functional properties.
Given the generic phrase “a derivative thereof having a nucleotide identity of at least 85%” as it relates to 5’ and 3’ untranslated region of the listed genes being incorporated into a recombinant nucleic acid construct, and the absence of teachings as to what specific nucleotides could be substituted, deleted, or otherwise modified while maintaining the desired functional properties, the Artisan would not understand Applicant to be in possession of the generic scope of “a derivative thereof having a nucleotide identity of at least 85%”.
Claims 1-20 are 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.
Claim 1 uses the generic phrase “effector molecule is effective in restoring cellular function or is effective in exercising a therapeutic effect in or on a cell” as it relates to restoring cellular function of a cell using the recombinant nucleic acid construct comprised of both 5’ and 3’ untranslated regions of cited genes. The same generic scope of “effector molecule is effective” is present in each of the dependent claims, i.e. Claims 2-4, 8-20.
Claim 13 uses the generic phrase “effector molecule is effective in restoring cellular function or is effective in exercising a therapeutic effect in or on a cell” as it relates to restoring cellular function of a cell using the recombinant nucleic acid construct comprised of both 5’ and 3’ untranslated regions of cited genes.
The specification provides antecedent basis for “effector molecule is effective in restoring cellular function or is effective in exercising a therapeutic effect in or on a cell” where the nucleic acid construct is able to restore cellular function [¶ 008].
Applicant’s specification states “…wherein the effector molecule is effective in restoring a cellular function of a cell or is effective in exercising a therapeutic effect in or on a cell” [¶ 008]. The specification further states that where the effector molecule that is effective in restoring cellular function is a mutant effector molecule [¶ 0022]. In paragraphs [0094] and [0095], Applicant’s specification states the effector molecule is effective as an autocrine factor or a paracrine factor. The specification further states that the “…recombinant nucleic acid construct according to the present invention comprising as the effector molecule this king of mutant effector molecule are particularly effective in the treatment of vascular leakage and any disease involving…or being caused by such vascular leakage” [¶ 00141]. However, the specification fails to provide or describe what is meant by “restoring cellular function”. The specification also fails to describe what is meant by “effective in exercising a therapeutic effect”. The specification provides no measurable parameters or criteria in which a therapeutic effect can be determined. The specification merely repeats claim language without further detailing how the cellular function is being restored or what cellular function is being restored. The specification does state that the effector molecule is effective in the treatment of vascular leakage, but again, it does not describe how the effector molecule restores cellular function. For example, Wang et al. discusses the importance of proteostasis in where protein synthesis, folding, trafficking, aggregation, and degradation are achieved in an optimal state of the cellular proteome [Using Pharmacological chaperones to restore proteostasis, Pharmacol Res., 2015, 1.1 Proteostasis in health and disease ¶ 1]. Additionally, proteostasis is crucial in achieving optimal concentrations, conformations, interactions, and locations that is made up of numerous subnetworks that also include cellular signaling pathways [1.2 Proteostasis maintenance by the proteostasis network ¶ 1]. Based on the foregoing, “restoring cellular function” encompasses a broad spectrum of biological processes, including stabilization of protein confirmation, correction of misfolded proteins, maintenance of proteostasis, and normalization of signaling pathways. The term “restoring cellular function” is not limited to a single mechanism but rather refers to any intervention that enables cells to regain or sustain activities such as protein synthesis, degradation, trafficking, energy metabolism, stress response, etc. And without further guidance, it would be difficult for a person of ordinary skill to determine what constitutes restoring cellular function. Are there specific cellular functions that would not be treated or would the effector molecule be effective in restoring all cellular functions?
Given the generic phrase “effector molecule is effective in restoring cellular function or is effective in exercising a therapeutic effect in or on a cell” as it relates to a recombinant nucleic acid construct with 5’ and 3’ untranslated regions of specific genes, and the absence of teachings of what cellular functions the effector molecule would be successful in restoring or exercising a therapeutic effect, an Artisan would not understand Applicant to be in possession of the generic scope of an “effector molecule is effective in restoring cellular function or is effective in exercising a therapeutic effect in or on a cell”.
Claims 4 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.
Claim 4 uses the generic term “P110” describing the mutant effector molecule and is optionally an engineered myristoylated form of the catalytic subunit P110alpha with respect to a recombinant nucleic acid construct with 5’ and 3’ untranslated regions of various genes.
The specification provides antecedent basis for “P110” as the mutant effector molecule [¶ 00190].
Applicant’s specification states “…the effector molecule is a mutant human PI 3-kinase which is referred to as myrP110*” [Id.]. It further states the myrP110* is based on a constitutively active PI 3-kinase molecule p110* carrying a myristylation signal, and that the P110* is a chimeric protein in which the iSH2 region of p85 is covalently linked to its binding site [Id.]. In paragraph [00193], the specification further lists the myrP110* as a myristoylated form of the catalytic subunit p110alpha. Lastly, paragraph [00513] in Fig. 105 shows a structure shows a recombinant nucleic acid construct PAN70 that comprises the 5’ non-translated region for the 5’ UTR of MCP-1 as the coding region for an effector molecule with the coding sequence for myrP110* along with a 3’ non-translated region. However, the claim lists this form of P110 as optional, yet the specification only discloses this species of P110. The specification does not mention non-myristoylated forms of P110. Further, the specification also does not disclose other catalytic subunits such as p110gamma, p110beta, or p110sigma [See Berndt et al., “The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors, 2010, Abstract]. The specification does not describe the structure or method for producing both non-myristoylated and myristoylated versions of these other catalytic subunits. Additionally, Wang et al. compared PI(3)K catalytic subunits with and without an N-terminal myristoylation [A pharmacological model reveals biased dependency on PI3K isoforms for tumor cell growth, Acta Pharmacol Sin., 2013, Results ¶ 1]. Wang et al. further disclosed that myristoylated PI3K versions are membrane-tethered and constitutively active, leading to Akt phosphorylation even in the absence of growth factors, such as serum free conditions [Id.]. On the other hand, non-myristoylated p110 requires upstream signaling from things such as serum or growth factors in order to activate Akt. In other words, without myristoylation, PI3K is dependent on regulatory interactions for subcellular localization and activation. Because of this and that that claim states the myristoylated P110 alpha is optional, an Artisan would not understand the metes and bounds based on the disclosure of Applicant’s specification.
Given the generic phrase “P110” in describing a mutant effector molecule where the P110 is optionally a myristoylated form of the catalytic subunit p110alpha, and the absence of teachings that other catalytic subunits could be used given the specification only describes the catalytic subunit p110alpha, an Artisan would not understand Applicant to be in possession of a mutant effector molecule that is a P110 other than the myristoylated catalytic subunit p110alpha.
Claims 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.
Claim 19 uses the generic phrase “treatment and/or prevention” as it relates to administering the recombinant nucleic acid construct of claim 1 for the purpose of eliciting a therapeutic effect.
The specification provides antecedent basis for “treatment and prevention” relating to treating disease by administering the recombinant nucleic acid construct [¶ 001].
Applicant’s specification states a pharmaceutical composition comprising the recombinant nucleic acid construct for use in a method for the treatment and/or prevention of disease [Id.]. The specification further states “the treatment and/or prevention of a disease, wherein the effector molecule is expressed by an endothelial cell” [¶ 0022]. The specification also states that an embodiment of the claimed invention also involves “treatment and/or prevention” of a disease through restoration of the cellular function of the cell [0023]. Lastly, the specification states that method for the “treatment and/or prevention” of a disease is by therapy [¶ 00116]. However, the specification does not disclose how the recombinant nucleic acid construct would affect treatment of a disease. The specification provides no experimental data or examples showing that the administration of the recombinant nucleic acid construct actually treats disease in a subject. Furthermore, the specification fails to provide any information on how the claimed invention would go about preventing disease. What parameters would an Artisan use to determine if a subject is in need of the claimed invention to prevent any disease or how the claimed invention would be administered. For example, Wang et al. discusses the use of a CRISPR/Cas-9 based genome editing therapy for several disease constructs such as Duschenne muscular dystrophy where a Dmd mutation was used to treat Duschenne muscular dystrophy [CRISPR/Cas-9 based genome editing for disease modeling and therapy: challenges and opportunities for nonviral delivery, Chemical Reviews, 2017, 3.2 Correcting monogenic disorders]. Muscular Dystrophy is an inherited X-linked disease caused by mutations in the gene encoding dystrophin [Id.]. Given that dystrophin is primarily expressed in skeletal and smooth muscle, where it functions to stabilize the sarcolemma during muscle contraction, Expression of a recombinant nucleic acid construct expressed in endothelial cells would not result in functional dystrophin production in the muscle tissue and would not be capable of restoring or replacing the mutated dystrophin protein in muscle cells. Because of this, the construct would not be able to treat or prevent Duchenne muscular dystrophy [“Dystrophin” Wikipedia 2019]. Based on this, an Artisan would not understand how the claimed invention would be capable of being administered for “treating and preventing” diseases.
Given the generic use of “treatment and/or prevention” as it relates to administering the recombinant nucleic acid construct, and the absence of teaching what parameters or guidance a person of ordinary skill would use to determine the efficacy for treating a disease or what parameters would be viewed to necessitate the administration of the claimed invention to have a prophylactic effect on disease, thus an Artisan would not understand Applicant to be in possession of the claimed invention with respect to administering the nucleic acid construct for “treatment and/or prevention” of disease.
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.
Claims 3, 8, 9, 10, 11, 13, 19 and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites the limitation "the mutant PIK3CA" in Line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 3 recites “PIK2CA E545K”. There is no recognized meaning in the art, and there is no recitation of PIK2CA in the specification. Furthermore, “PIK2CA” is not listed in the HUGO Gene Nomenclature Committee database.
Claim 8 recites “wherein the construct comprises a poly-A tail”. However, the claim then states “wherein said poly-A tail optionally is located at the 3’ terminal end…”. This is ambiguous. Is the claim stating that poly-A tail is optional? Or is the claim stating that somehow the poly-A tail can be located anywhere other than the 3’ terminal end? And if so, how is the poly-A tail located anywhere other than the 3’ terminal end. A person of ordinary skill would not understand what “wherein said poly-A tail optionally is located at the 3’ terminal end…” would mean.
Claim 9 recites “wherein said CAP structure optionally is at the 5’ terminal end…”. This is ambiguous. Is the claim stating the CAP structure is optional? Or is the claim stating that somehow the CAP can be located somewhere other than 5’ terminal end? And if so, how is the CAP located anywhere other than the 5’ end, and how is it able to function in its respective manner? An Artisan would not be able to understand the claim language as written.
Claim 10 recites “wherein optionally said IRES is at the 5’ terminal end…”. Again, this is ambiguous. Is the IRES optional? Does this mean the CAP can be placed after the UTR or even at the 3’ terminal end? And if so, how does it retain its function? Is it able to be located before the CAP of the 5’ terminal end? An Artisan would not understand the claim language as written.
Claim 11 recites “wherein optionally said signal peptide is in-frame with nucleic acid sequence coding…and is arranged between the 5’ UTR and the coding region for the effector molecule”. Is the signal peptide itself optional? Or is the signal peptide allowed to be located anywhere other between the 5’ UTR and coding region for the effector molecule? Is it allowed to be located between the coding region and 3’ UTR or between the 3’ UTR and poly-A tail? An artisan would not understand the claim language as written.
Claim 11 recites the limitation "nucleic acid sequence" in Lines 2 and 3. There is insufficient antecedent basis for these limitations in the claim.
Claim 11 recites “…optionally said signal peptide is in-frame with nucleic acid sequence coding…”. This language is unclear. A signal peptide is inherently in-frame with itself. This creates ambiguity as to the intended scope of the claim. It is unclear whether the signal peptide is to be in-frame with another sequence, e.g. a downstream coding sequence, or if another feature is meant by the language. An Artisan would not understand what Applicant means as the claim is written.
Claim 13 recites “wherein the cell a cellular function is restored”. This language is grammatically ambiguous. Additionally, the claim is not specifying what cellular function is being restored and the specification provides no measurable objectives in which an Artisan could determine what would constitute “cellular function is restored”.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same 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 § 2173.05(c). In the present instance, claim 17 recites the broad recitation “nanoparticle is from about 30 nm to about 200 nm, and the claim also recites “from about 30 nm to about 140 nm” or “about 30 nm to about 60 nm” which is the narrower statement of the range/limit