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 .
DETAILED ACTION
This Office Action is a response to Applicant’s Preliminary Amendment filed August 30, 2023. Claim 11 has been canceled. Claims 7-10 and 12-16 have been amended.
Claims 1-10 and 12-16 are pending in the instant application.
Claims 1-10 and 12-16 have been examined on the merits as detailed below:
Information Disclosure Statement
Applicant's information disclosure statement (IDS) filed April 5, 2023 is acknowledged. The submission is in compliance with the provisions of 37 CFR §1.97. Accordingly, the Examiner has considered the information disclosure statement, and a signed copy is enclosed herewith.
Drawings
The Drawings filed on June 25, 2025 are acknowledged. The Drawings are objected to because some Drawings reference the colors, "red", "blue", "green" and “purple”. See Figures 2b, 2f and 6c, for example. In the instant application, color drawings have been filed without an accompanying petition. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Color photographs and color drawings are not accepted unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), three sets of color drawings or color photographs, as appropriate, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37CFR 1.84(b)(2). Note that the requirement for three sets of color drawings under 37 CFR 1.84(a)(2)(ii) is not applicable to color drawings submitted via EFS-Web. Therefore, only one set of such color drawings is necessary when filing via EFS-Web.
Claim Objections
Claim 2 is objected to because of the following informalities: Reference to a specific Figure or Table “is permitted on in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim”, see MPEP 2173.05(s). Appropriate correction is required.
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 10 and 12 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. This is an enablement rejection.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988).
Wands states on page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
Claim 10 is drawn to a method to treat, prevent or ameliorate the effects of a disease associated with ACE2 expression, comprising the step of: a) administering to the subject an effective amount of one or more antisense oligomers or pharmaceutical composition comprising an isolated or purified antisense oligomer for modifying pre-mRNA splicing in the Angiotensin Converting Enzyme 2 (ACE2) to modulate splicing of the ACE2 gene transcript or part thereof which has a modified backbone structure and sequences with at least 75% sequence identity to such antisense oligomers and which have a modified backbone structure. Claim 12 is drawn to a kit to treat, prevent or ameliorate the effects of a disease associated with ACE2 expression in a subject, which kit comprises at least an isolated or purified antisense oligomer for modifying pre-mRNA splicing in the Angiotensin Converting Enzyme 2 (ACE2) to modulate splicing of the ACE2 gene transcript or part thereof which has a modified backbone structure and sequences with at least 75% sequence identity to such antisense oligomers and which have a modified backbone structure and combinations or cocktails thereof, packaged in a suitable container, together with instructions for its use. The inventions are in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
It should be made clear that, the enabling specification must teach those skilled in the art to make and use the full scope of the claimed invention without undue experimentation. “Although not explicitly stated in section 112, to be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without "undue experimentation." Vaeck, 947 F.2d at 495, 20 USPQ2d at 1444; Wands, 858 F.2d at 736-37, 8 USPQ2d at 1404; In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (the first paragraph of section 112 requires that the scope of protection sought in a claim bear a reasonable correlation to the scope of enablement provided by the specification).” In re Wright (CAFC) 27 USPQ2d 1510 at 1513. Although a working example is not required to enable an invention, the skilled artisan must be able to practice the claimed invention without undue experimentation. See also, MPEP §2164.02, which states in part: The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970). Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
The prior art does not teach a method to prevent the effects of a disease associated with ACE2 expression in a subject, comprising the step of: a) administering to the subject an effective amount of one or more antisense oligomers or pharmaceutical composition comprising an isolated or purified antisense oligomer for modifying pre-mRNA splicing in the Angiotensin Converting Enzyme 2 (ACE2) to modulate splicing of the ACE2 gene transcript or part thereof which has a modified backbone structure and sequences with at least 75% sequence identity to such antisense oligomers and which have a modified backbone structure.
The present description provides examples of the modulation of splicing of ACE2 using antisense oligonucleotides in cultured cells (in vitro). See Examples 2-6. The application also teaches male C57bl6 mice intratracheally administered (in vivo) an antisense construct specific to the mouse ACE2 mRNA sequence and an induction of alternative splicing of ACE2 was observed in the lungs. See FIG. 5f. The data presented in the Specification does not rise to the level of prevention. Regarding “preventing” disorder/disease, it is noted that “preventing” encompasses complete (i.e., 100%) and permanent prevention. One of skill in the art would recognize that the complete prevention of any disease, including one involving the effects of a disease associated with ACE2 expression in a subject would be very difficult and there would be a low level of expectation of success (i.e., highly unpredictable).
The specification does not provide any working example demonstrating prevention of the effects of a disease associated with ACE2 expression in a subject. Therefore, given the lack of knowledge present in the prior art and the lack of guidance provided in the specification with respect to preventing the effects of a disease associated with ACE2 expression, further experimentation would be required. Considering that the additional experimentation would require de novo experimentation without a guarantee of success, and further considering that any positive results (i.e., successful disease prevention in a subject) would amount to a significant advancement in the state of the art, the additional experimentation required is considered undue.
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004).
Furthermore, in In re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case here where there is a relatively incomplete understanding in the biotechnological field involved, as described above, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims.
Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention. Therefore, it is appropriate to reject the claims under 35 USC 112(a) for not being enabled.
Thus, in view of the breadth of the claims, the lack of guidance, and the lack of working examples, the instant specification is not found to be enabling for the prevention of the effects of a disease associated with ACE2 expression in a subject. It would require undue experimentation and making a substantial inventive contribution for the skilled artisan to discover how to make and/or use the claimed invention in its full scope.
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Claims 1-10 and 12-16 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. This is a written description rejection.
The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirement for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice..., reduction to drawings..., or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the disclosure must provide written support for the entire scope of the genus. Support for a genus is generally found where the Applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed and that applicant was in possession of the claimed genus.
The instant claims are drawn to an isolated or purified antisense oligomer for modifying pre-mRNA splicing in the Angiotensin Converting Enzyme 2 (ACE2) to modulate splicing of the ACE2 gene transcript or part thereof which has a modified backbone structure and sequences with at least 75% sequence identity to such antisense oligomers and which have a modified backbone structure and a kit comprising said isolated or purified antisense oligomer and methods of administering said isolated or purified antisense oligomer to a subject. There is insufficient written description of the isolated or purified antisense oligomer encompassed by the claims. The present Specification discloses antisense oligonucleotides comprising SEQ ID NOs. 1-31, but does not describe sequences with at least 75% sequence identity that function as antisense oligomers for modifying pre-mRNA splicing in ACE2 to modulate splicing of the ACE2 gene transcript as claimed.
Written description requirement for claims that recite sequences with at least 75% sequence identity that function as antisense oligomers for modifying pre-mRNA splicing in ACE2 to modulate splicing of the ACE2 gene trans is not met because the Specification does not provide any description of any variants or what sequences could be modified (added, deleted or mutated) that retain function. Accordingly, the claims encompass using a genus of antisense oligomers which are not adequately described. The claims are rejected because there is insufficient description of the genus of antisense oligomers encompassed by the claims.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). It is noted that conception is not achieved until reduction to practice has occurred regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
To satisfy the written description requirement an applicant must describe the invention is such a way as to convey to one skilled in the art that applicant had the invention in his possession when the application was filed. Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc). In cases such as the instant application where a genus is claimed, the specification must contain “either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350. However, written description requirement for claims that recite a percent identity to antisense oligomer for modulating mRNA translation of the optic atrophy 1 (OPA1) gene transcript is not met.
The entire genus of antisense oligomer sequences with at least 75% sequence identity that function as antisense oligomers for modifying pre-mRNA splicing in ACE2 to modulate splicing of the ACE2 gene transcript as claimed does not exist in the instant application. That is, adequate written description support does not exist to practice the full scope of the invention claimed. The specification nor the art discloses neither a representative number of species compounds nor any structure/function correlation that would enable one of skill to immediately envision the genus antisense oligomers required to practice the full scope of the invention.
As stated above, the MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic claim. Given the breadth of the claims, the Specification lacks sufficient variety of species to reflect the variance in the genus.
In conclusion, the Specification and the prior art as filed does not provide sufficient descriptive support for the myriad of antisense oligomers embraced by the claims. For the reasons discussed above, the 35 USC § 112 rejection for written description is applicable.
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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3-10 and 12-15 rejected under 35 USC § 102 (a)(1) as being anticipated by U.S. Patent Publication 2007/0238681 (submitted and made of record on the IDS filed April 5, 2023).
The claims are drawn to an isolated or purified antisense oligomer for modifying pre-mRNA splicing in the Angiotensin Converting Enzyme 2 (ACE2) to modulate splicing of the ACE2 gene transcript or part thereof which has a modified backbone structure and sequences with at least 75% sequence identity to such antisense oligomers and which have a modified backbone structure and a kit comprising said isolated or purified antisense oligomer and methods of administering said isolated or purified antisense oligomer to a subject.
U.S. Patent Publication 2007/0238681 is directed towards the modulation of ACE2 expression (see Abstract). U.S. Patent Publication 2007/0238681 discloses antisense oligonucleotide compounds that target ACE2 and that said compounds can be administered in methods of modulating ACE2 expression for the treatment (therapeutic and prophylactic) of diseases and conditions associated with ACE2 expression, and also in a method of inhibiting a SARS coronavirus (see [0015-0018]).
U.S. Patent Publication 2007/0238681 discloses a range of antisense compounds, including alternate splicers, that may be introduced to a cell to effect modification of the target ACE2 nucleic acids (see [0030] and [0182]). Further, the antisense compounds of U.S. Patent Publication 2007/0238681 induce splicing of the RNA to yield one or more RNA species and it is also disclosed that introns can be effectively targeted using antisense compounds.
U.S. Patent Publication 2007/0238681 further discloses that both ACE2 mRNA, pre-mRNA and splice variants are suitable targets for the antisense oligonucleotides of the invention (see [0048-0052]).
U.S. Patent Publication 2007/0238681 discloses that the antisense oligonucleotides can have a range of modifications including modified sugars, conjugates to other moieties, resistance to nuclease degradation and oligomeric mimetic chemistries, and that they may have uracil codons replaced with thymine (see [0015], [0072-0089], [0180] and examples 2-5). Modifications include 2'-MOE-modified antisense oligonucleotides (ASOs) or ASOs comprising phosphorothioate internucleoside linkages, for example. Kits comprising ACE2 targeting antisense compounds [e.g. 0130], and compositions comprising antisense compounds and a pharmaceutically acceptable diluents or carriers are also disclosed (e.g. see [0070] and [0130]).
U.S. Patent Publication 2007/0238681 discloses antiviral drugs may also be combined in compositions of the invention. Further, it is disclosed that combinations of antisense compounds are also within the scope of their invention.
Claims Free of the Prior Art
Claims drawn to an isolated or purified antisense oligomer for modifying pre-mRNA splicing in Angiotensin Converting Enzyme 2 (ACE2) to modulate splicing of the ACE2 gene transcript, wherein the antisense oligomer has a modified backbone structure, wherein the antisense oligomer is a combination of antisense oligomers, and wherein the combination of antisense oligomers is chosen from the combination SEQ ID NO: 6 and 9 or SEQ ID NO: 6 and 11 are free of the prior art.
Conclusion
No claims are allowable at this time.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Terra C. Gibbs whose telephone number is 571-272-0758. The Examiner can normally be reached from 8 am - 5 pm M-F.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Ram Shukla can be reached on 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TERRA C GIBBS/Primary Examiner, Art Unit 1635