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
Election/Restrictions
Applicant's election without traverse of Group I, SEQ ID No. 1 and 52 in the reply filed on 06/03/2026 is acknowledged.
Status of the Application
Claims 1, 4, 7, 10, 12, 13, 15, 18, 19, 23, 24, 26, 29, 36, 42, 48, 50 and 54 are pending and are currently under examination.
Specification Objections
The disclosure is objected to because: the structures representing PPMO#1-4 on pages 32-34 are in small font and therefore illegible. The structures do not clearly illustrate each base, sugar or linkages clearly to be capable of determining the exact structure.
Applicant is required to correct these errors. This is not an extensive search for grammatical errors in the specification and Applicant is encouraged to review the specification and make corrections if appropriate.
Claim Rejections – Improper Markush
Claims 29, 36 and 42 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: The claims are directed to a large multitude of sequences that have no common searchable structure and are to different exons and different regions of an exon. Although the sequences are made up of the same four bases, they do not share any significant similarity in the order in which those bases are arranged. Thus, the structures of the sequences are different.
When the Markush grouping is for alternatives of chemical compounds, they shall be regarded as being of a similar nature where the following criteria are fulfilled:
(A) All alternatives have a common property or activity; and
(B) (1) A common structure is present, i.e., a significant structural element is shared by all of the alternatives; or
(B) (2) In cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
In paragraph (B)(1), above, the words “significant structural element is shared by all of the alternatives” refer to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity. The structural element may be a single component or a combination of individual components linked together.
In paragraph (B)(2), above, the words “recognized class of chemical compounds” mean that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
In order for the members of the Markush group to belong to “recognized class of chemical compounds” there must be an expectation that the members of the class will behave in the same way in the context of the claimed invention. In other words, each member of the class could be substituted one for the other with the expectation that the same intended result would be achieved. In the instant case, activity of any specific nucleic acid molecule is dependent upon the specific sequence of nucleotides. There is no expectation that any one of the nucleotide sequences as claimed can be substituted for any of the other with a completely different sequence with the expectation of the same activity.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. 134 and 37 CFR 41.31(a)(1).
Claim Rejections - 35 USC § 102
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 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 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.
Claim(s) 1, 4, 7, 13, 23, 24, 26, 29, 36, 42 and 50 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Passini et al. (US Application No. 20180177814).
Regarding claims 1, 4, 7 and 13, Passini et al. teach an antisense oligonucleotide conjugate comprising a cell-penetrating peptide or a pharmaceutical acceptable salt thereof (0015, 0024) wherein the compositions may be mixed with one or more of citrate, sucrose and poloxamer (0224).
Regarding claim 23, Passini et al. teach the antisense oligonucleotides in a dose of 10-160 mg/kg which is in the range of the claimed limitation (0244).
Regarding claim 24, Passini et al. teach the antisense oligonucleotides are capable of exon skipping in the human dystrophin gene (0019).
Regarding claim 26, Passini et al. teach the oligonucleotides can comprise a cell penetrating arginine rich peptide having SEQ ID No. 52 (0091, 0022 and SEQ ID No. 4 page 68).
Regarding claim 29, Passini et al. teach the oligonucleotide conjugate is of Formula I having a morpholino structures wherein the cell penetrating arginine rich peptide is attached at R (0160-0163) and teach instant SEQ ID No. 1 (0170).
Regarding claim 36, Passini et al. teach Formula II with Nu being SEQ ID No. 1 (see 0172-0176).
Regarding claim 42, Passini et al. teach instant Formula III wherein Nu is SEQ ID No. 1 (0184-0194).
Regarding claim 50, Passini et al. teach the antisense oligonucleotides conjugate is a pharmaceutically acceptable salt (0208).
Thus Passini et al. anticipates the instant claims.
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 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 10, 12 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Passini et al. (US Application No. 20180177814) in view of Poecheim et al. ("Development of stable liquid formulations for oligonucleotides." European Journal of Pharmaceutics and Biopharmaceutics 129 (2018): 80-87).
Passini is relied upon as above but does not teach the pH and buffers suitable for the oligonucleotide.
Regarding claims 10, 12 and 15, Poecheim et al. teach to develop stable liquid formulations for oligonucleotides, it is important to determine the pH and buffers suitable for the oligonucleotide and teach ranges of pH of 6.5-10 and buffers of 20 mM (see page 81-82). It would have been obvious to use these ranges and concentrations with the oligonucleotide taught by Passini et al. to develop a stable and efficient oligonucleotide for use in exon skipping.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Claim 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Passini et al. (US Application No. 20180177814) in view of Brus et al. ("Stabilization of oligonucleotide–polyethyleneimine complexes by freeze-drying: physicochemical and biological characterization." Journal of Controlled Release 95.1 (2004): 119-131).
Passini is relied upon as above but does not teach lyophilization.
Regarding claim 18, Brus et al. teach nucleic acid conjugates for delivery to cells suffer from instabilities that include aggregation tendencies and loss of transfection efficiency, thus requiring preparation directly prior to injection and states under these conditions, essential standards for pharmaceutical products, such as reproducibility and controlled quality are hardly guaranteed (introduction pages 119-120). Brus et al. demonstrates that lyophilization is a very potent technique to produce stable conjugates (see conclusion). It would have been obvious to one of ordinary skill in the art to lyophilize the antisense oligonucleotide conjugate to increase stability for use in exon skipping and one would have been capable of doing so given the steps of which are taught in the prior art.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
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 19, 48 and 54 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 pre-AIA the applicant regards as the invention.
Claims 19 recites “wherein the composition dissolves within 30 minutes after addition of an aqueous solvent and depends from claim 1. This limitation is unclear because claim 1 does not recite the composition is in a dry or powder form that when administered with a solvent, would dissolve. Thus the claim is indefinite and will not be further examined on the merits because it cannot be ascertained, without assumption, what further limitations are in the claim.
Claims 48 and 54 recite PPMO#1-4 and is indefinite because it is unclear what sequences these represent. The specification at pages 32-34 recite the same conjugate but does not provide a corresponding sequence. Thus the claim will not be further examined on the merits because it cannot be ascertained, without assumption, what further limitations are in the claim.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
Written Description
Claim 24 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious" and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966; Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial Structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and v. Correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art.
Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species 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 functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed 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.
The claims are drawn to a genus of compositions comprising an antisense oligonucleotide, a cell penetrating peptide, one or more surfactants, one or more sugars and one or more buffering agents with the function of binding a selected target to induce exon skipping in the human dystrophin gene.
When determining whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, the specification describes a composition comprising an antisense oligonucleotide conjugated with varying amounts of sucrose, mannitol and polysorbate (Example 4) but does not describe this composition as capable of targeting a gene to induce exon skipping. Therefore this example does not encompass the vast number of different compositions as claimed.
It is then determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genera. In the instant case, the only other identifying characteristics are appearance of lyophilized product, moisture constitution and time of reconstitution in Tables 9-12. Such functional limitations cannot be the only identifying characteristics for the vast number of expression constructs claimed. A review of the specification shows that it provides no description or guidance that would allow one of skill to distinguish the functional species of the recited structural genus from the non-functional members without empirical determination.
Since the disclosure and the prior art fail to describe the common attributes and characteristics concisely identifying members of the proposed genus, and because the claimed genus is highly variant a vast number of compositions comprising any variation of sequences, surfactants, sugars and buffers that are targeted to any selected target of a human dystrophin gene, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus claimed.
"A sufficient description of a genus . . . requires the disclosure of 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" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
Further, “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” Ex parte Kubin, 83 USPQ2d 1410, 1417 (Bd. Pat. App. & Int. 2007) citing University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “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).
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
Thus the specification and claims lack written description because it is clear that Applicant did not have possession of every variation of the compositions. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521,222 USPQ 369,372-372 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the entire scope of the claimed invention.
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. See 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);and, 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this 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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 4, 7, 10, 12, 13, 15, 18, 19, 23, 24, 26, 29, 36, 42, 48, 50 and 54 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-8 and 12-30 of U.S. Patent No. 10,888,578 (PAT578). Although the conflicting claims are not identical, they are not patentably distinct from each other because the instant claims and the claims of the patent are drawn to patently indistinguishable subject matter
MPEP 804 “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 determining whether a nonstatutory basis exists for a double patenting rejection, the first question to be asked is: Is any invention claimed in the application anticipated by, or an obvious variation of, an invention claimed in the patent? If the answer is yes, then a nonstatutory double patenting rejection may be appropriate.”
PAT578 teach methods of treating Duchenne muscular dystrophy and restoring and mRNA reading frame to induce dystrophin production comprising administering an antisense oligonucleotide conjugate having SEQ ID No. 1 and an arginine rich peptide comprising SEQ ID No. 4. The instant claims are drawn to an antisense oligonucleotide conjugate having SEQ ID No. 1 and an arginine rich peptide comprising SEQ ID No. 52 which is identical to SEQ ID No. 4. It would have been obvious variation to use the instant antisense oligonucleotide conjugate in the methods of PAT578. The Court of Appeals for the Federal Circuit in Pfizer Inc, v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001 at page 1008 (March 2008), indicated that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application.
Conclusion
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/KIMBERLY CHONG/
Primary Examiner Art Unit 1636
Prosecution Insights