DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
NOTE: the examiner for this application has changed. Please address all future correspondence to Examiner Ruthie Arieti, AU1635.
Claims 1-29 are pending.
Election/Restrictions
Applicant’s election of the invention Group I (Claims 1-26) and the species SEQ ID NOs 4, 10, 18, 24, 78, and 132 in the reply filed on 17 December 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 27-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 17 December 2025.
Regarding Claim 20:
SEQ ID NO 36 is found to be a modified version of elected SEQ ID NO 4,
SEQ ID NO 50 is found to be a modified version of elected SEQ ID NO 18,
SEQ ID NO 42 is found to be a modified version of elected SEQ ID NO 10, and
SEQ ID NO 46 is found to be a modified version of elected SEQ ID NO 24.
Claims 1-26 are examined.
Information Disclosure Statement
The Spec. cites references.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The IDS(es) has been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See p. 53 ¶4. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Interpretation
The claims recite portions that are at least partially complementary with other portions. At least partial complementarity is broadly interpreted as requiring at least one nt of complementarity.
All positions are interpreted to count from the 5’ end unless the claim specifies otherwise.
All limitations before or after and/or are interpreted as fully optional. (Only one of the recited limitations is require to meet the claim.)
All optional limitations are interpreted as fully optional. See §112b for more information.
Claim 1 recites at least one labile functionality… wherein said labile functionality comprises one or more unmodified nucleotides [nt].
Any one or more unmodified nt is interpreted as being a labile functionality.
Claim 1 and claims depending therefrom recite a first nucleic acid portion that is at least partially complementary to… a first portion of an RNA which is transcribed from a PCSK9 gene… a second nucleic acid portion that is at least partially complementary to… a second portion of an RNA which is transcribed from a APOC3 gene… first nucleic acid portion… second nucleic acid portion.
The first and second nucleic acid portion[s] that is at least partially complementary are interpreted as distinct from the first and second portion[s] of an RNA which is transcribed from a [PCSK9 or APOC3] gene…. The first and second nucleic acid portion[s] that is at least partially complementary are interpreted as each forming a nucleic acid duplex (with the third and fourth nucleic acid portions) whereas the first and second portion[s] of an RNA which is transcribed from a [PCSK9 or APOC3] gene are interpreted as referring to the target mRNA. Applicant should see §Claim objections to improve the claim.
Similarly, Claims 7-8 recite 1-8 additional nucleic acid portions that are respectively at least partially complementary to an additional 1-8 portions of RNA transcribed from one or more target genes and wherein each of the 1-8 additional nucleic acid portions respectively form additional duplex regions with respective passenger nucleic acid portions.
The 1-8 additional nucleic acid portions that are respectively complementary… are interpreted as distinct from the additional 1-8 portions of RNA transcribed from one or more target genes …. The 1-8 nucleic acid portion[s] that are respectively complementary are interpreted as each forming a nucleic acid duplex (with their respective passenger strand nucleic acid portions) whereas the additional 1-8 portions of RNA transcribed from one or more target genes are interpreted as referring to the target mRNA.
Claim 10 recites …cleavage occurs at the 3’ position of said unmodified nt. The 3’ position is interpreted to be the 3’ end of the nt (as opposed to the 5’ end of the nt or the 3’ carbon of the nt).
Claim 21 recites …two strands… the first strand…the second strand…. The recitation two strands is interpreted to provide antecedent basis for the first strand and the second strand.
Claim Objections
Claims 1-2, 7-8, 10, 12, 14-16, 21, and 25-26 are objected to because of the following informalities:
Claim 1: the claim will be better if it reads:
…(a) a first nucleic acid portion that is at least partially complementary to at least a portion of an RNA which is transcribed from a PCSK9 gene;
(b) a second nucleic acid portion that is at least partially complementary to at least a portion of an RNA which is transcribed from a APOC3 gene…
Eliminating the second instances of first portion and second portion (when they’re used to refer to the transcribed RNA rather than the components of the dsRNA) will make the claim better.
Claim 1 should spell out PCSK9 and APOC3. In the interest of compact prosecution PCSK9 is interpreted as Proprotein Convertase Subtilisin/Kexin Type 9 and APOC3 is interpreted as Apolipoprotein C3.
Claim 1 should also hyphenate discrete nucleic acid-targeting molecules in the third-to last line.
Claim 2: items (c) and (d) should include spaces so they read … (c)… 21 and SEQ ID NO … (d) … 28 and SEQ ID NO 30.
Claim 7: the claim should be amended so each [singular] agrees with forms in L3-4.
Claim 8: remove the commas after (b) and between portions are.
Claim 10: the claim will be better if it’s changed to remove “involves”: …wherein said inter-nt bond links at least one of said one or more unmodified nt…
Claim 12: the claim should recite …are at any of positions 18-25…
Claim 14: the claim will be better if it recites …the construct according to Claim 13, comprising…
Claim 15: the claim should remove any of claims 14 and should simply recite: the construct according to Claim 14, comprising…
Claim 16: the recitations to the extent present should be replaced with any of the [1 to 8…, the passenger…, …the nucleic acid linker…].
Claim 21: the claim needs to insert from in L2 so it recites …and the second strand from the group consisting of…
Claim 25: the claim should replace furthermore with further and remove the second instance of further so it recites …composition further comprises one or more pharmaceutically active agents.
Claim 26: the word “as” is missing from …fibrates such as fenofibrate. (See §112b)
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 1-26 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.
Claim 1 recites nucleic acid portion[s] that are at least partially complementary to at least a first portion of an RNA… from a PCSK9 gene and to …at least a second portion of an RNA… from a APOC3 gene…, third and fourth nucleic acid portion[s] that are at least partially complementary to said first or second portion[s] of a/b… so as to form a first nucleic acid duplex region therewith. The claim specifies that the construct is cleaved so as to yield at least first and second discrete nucleic acid targeting molecules.
Claims 2-6 and 20-21 recite the portions have specific nucleobase sequences: SEQ ID NOs 4, 10, 18, 24, 78, or 132.
Broad Claims 1 and claims depending therefrom (Claims 3 and 7-26) encompass the large genera of “first/second nucleic acid portions” that are “at least partially complementary” to a “first/second portion” of an RNA target (which is transcribed from a PCSK9 or APOC3 gene) and the broad genera of third/fourth nucleic acid portions that are at least partially complementary to the first/second nucleic acid portions and form duplex regions with them. The claims encompass structures that are cleaved so as to yield at least first/second discrete nucleic acid-targeting molecules.
Any kind of nucleic acid that has any complementarity to the recited target mRNAs would be encompassed by the claims as instantly presented. The target PCSK9 and APOC3 mRNAs comprise every nt base, so even a single nt represents a portion that is at least partially complementary to the target sequences and can form a duplex region therewith. Therefore the claims encompass literally any nucleic acid sequence in existence or future existence.
There is a written description (WD) problem with the claims because neither the claims nor the Spec. disclose what requisite structure(s) constitute the various portion[s] or portion[s] that is at least partially complementary to the target or form duplex regions. The claims recite nucleic acid portions that are identified solely by their functional characteristics of being at least partially complementary to portions of RNA transcribed from a target gene, portions of RNA transcribed from a target gene, and portions that are at least partially complementary with other portions so as to form duplexes. However, the Spec. doesn’t describe what structures are responsible for those functional characteristics: what constitutes a “portion” of an RNA transcribed from the recited target genes or what amount of partial complementarity is sufficient for forming a duplex region or the characteristics of that region. Nor does the Spec. demonstrate possession of a representative number of the nucleic acid portions encompassed by the claims. The Spec. doesn’t disclose any length or structural requirements for the various nucleic acid portions or portions of an RNA.
Regarding the limitation that the construct is cleaved so as to yield at least first and second discrete nucleic acid targeting molecules, that has a WD problem because it recites nucleic acid constructs that are identified solely by their function of being cleaved so as to yield at least first/second discrete nucleic acid-targeting molecules but does not disclose what structure(s) are cleaved to form at least first and second discrete nucleic acid targeting molecules.
Claims 3, 5, and 8 recite some of the various nucleic acid portions are linked as a primary structure or as respective primary structures.
Those broad claims encompass the large genus of ways of linking nucleic acids so as to form primary structures or respective primary structures. Any kind of nucleic acid linking modality that links nucleic acids so as to form primary structures or respective primary structures would be encompassed by the claims as instantly presented.
There is a WD problem because the claims recite nucleic acid linking modalities that are identified solely by their function of linking nucleic acids so as to form primary structures or respective primary structures, but the Spec. doesn’t disclose what structure is responsible for that function.
Claims 7-8 recite 1-8 additional nucleic acid portions that are respectively at least partially complementary to an additional 1-8 portions of RNA transcribed from one or more target genes and wherein each of the 1-8 additional nucleic acid portions respectively form additional duplex regions with respective passenger nucleic acid portions.
Those broad claims encompass the large genus of “nucleic acid portions” that are “at least partially complementary” to any additional target. Any kind of nucleic acid that has any complementarity to any target mRNAs besides PCSK9 or APOC3 would be encompassed by the claims as instantly presented. The encompassed mRNAs comprise every nt base, so even a single nt represents a portion that is at least partially complementary to the target sequences. Therefore the claims encompass literally any nucleic acid sequence in existence or future existence.
There is a written description (WD) problem with the claims because neither the claims nor the Spec. disclose what requisite structure(s) constitute a portion that is at least partially complementary to the target and because a huge number of target genes are encompassed by the claims. Nor does the Spec. demonstrate possession of a representative number of the nucleic acid portions encompassed by the claims.
Regarding the limitation that the portions respectively form additional duplex regions with respective passenger nucleic acid portions, that has a WD problem because it does not disclose what structure(s) form duplex regions or what structures comprise respective passenger nucleic acid portions. All of the WD problems discussed above that apply to Claim 1 and claims depending therefrom also apply to Claims 7/8.
Claim 8 recites the second nucleic acid portion of (b) and the said 1-8 additional nucleic acid portions are linked to selected passenger nucleic acid portions as respective primary structures.
That broad claim encompasses the large genus of passenger nucleic acid portions that are selected. Any kind of passenger nucleic acid portion that is selected would be encompassed by the claims as instantly presented.
There is a WD problem because the claims recite a broad genus of nucleic acid portions identified solely by their functional characteristics of being linked to selected passenger nucleic acid portions as respective primary structures but the Spec. doesn’t disclose what structure(s) comprise passenger nucleic acid portions or selected passenger nucleic acid portions.
Claim 25 recites a pharmaceutical composition that further comprises one or more further pharmaceutically active agents.
That encompasses the broad genus of additional agents that are pharmaceutically active. Any kind of pharmaceutically active agent would be encompassed by the claims as presented. There is a WD problem because the claim encompasses a large genus of agents identified solely by their function of being pharmaceutically active but the Spec. doesn’t disclose any structure(s) responsible for that function.
Claim 26 recites …an RNAi agent which is directed to a different target from PCSK9 and from APOC3; and/or wherein said agent(s) comprise a lipid-lowering agent….
That broad claim encompasses the large genus of RNAis that are directed to any target other than PCSK9 and APOC3. The broad claim encompasses the large genus of lipid-lowering agents. Any kind of RNAi or lipid-lowering agent would be encompassed by the claims as instantly presented.
There is a WD problem because the Spec. doesn’t disclose a representative number of RNAi agents directed to targets other than PCSK9 and APOC3. The claim recites a genus of RNAi agents identified solely by their function of inducing RNAi but the Spec. doesn’t disclose a structure that underlies that function. RNAi encompasses an ability to inhibit a target gene and the claims encompass RNAi that inhibit any target gene. There is a WD problem because the claim recites a genus of agents identified solely by their function (i.e., lipid-lowering agents) but the Spec. doesn’t disclose any structure that underlies that function.
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). 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. See MPEP 2163.
The Spec. provides (p. 18 ¶1) the following definition for “portion”:
As used herein, "region" or "regions", or "portion" or "portions", mean a plurality of linked nucleosides that have a function or character as defined herein, in particular with reference to the claims and definitions as provided herein. Typically such regions or portions comprise at least 10, at least 11, at least 12 or at least 13 linked nucleosides. For example, such regions can comprise 13 to 20 linked nucleosides, such as 13 to 16 or 18 to 20 linked nucleosides. Typically a first region as defined herein consists essentially of 18 to 20 nucleosides and a second region as defined herein consists essentially of 13 to 16 linked nucleosides.
However, that definition doesn’t resolve the WD problem because a plurality of linked nucleosides that have a function or character as defined herein, in particular with reference to the claims and definitions as provided herein doesn’t define any physical structure required by the claims.
The Spec. doesn’t disclose what structure(s) constitute a portion that is at least partially complementary to at least a portion of an RNA transcribed from PCSK9/APOC3/any other target gene. The Spec. doesn’t disclose what structure(s) constitute a portion of an RNA transcribed from PCSK9/APOC3/any other target gene. The Spec. doesn’t disclose what structure(s) constitute partial complementarity to the recited nucleic acid portions or what structures are required to form suitable duplex regions with them. The Spec. doesn’t disclose what structures comprise portion[s] or portion[s] suitable to use in the nucleic acid constructs.
Regarding the limitation that the regions form duplex regions or portions respectively form additional duplex regions with respective passenger nucleic acid portions, the Spec. doesn’t disclose the structures that form duplex regions or what is structure is required for forming a suitable duplex region. Is a duplex region of a single base pair sufficient? How much partial complementarity is required to form a suitable duplex region? An artisan wouldn’t know because the Spec. doesn’t disclose that information.
Regarding the limitation that the construct is cleaved so as to yield at least first and second discrete nucleic acid targeting molecules, the Spec. doesn’t disclose the structure that yields at least first and second discrete nucleic acid targeting molecules. The Spec. minimally teaches about that limitation (pp. 22-23 L14-11) but that doesn’t provide any information about the structure of the what is cleaved and how it yields the two discrete nucleic acid targeting molecules.
Regarding the nucleic acid linking modality that links nucleic acids as a primary structure or respective primary structure, the Spec. doesn’t disclose any information about linker structure, what comprises a primary structure, how the linking modality forms a primary structure, or how a primary structure differs from a non-primary structure. A person of ordinary skill knows there are many kinds of linkers that connect nucleic acids (see IntegrateRNA. Cleavable Linkers for Oligonucleotide Conjugation. Available online at integraterna.creative-biogene.com. Accessed on 21 May 2026) and while the claims encompass all of them, it’s not clear that Applicant was in possession of a representative number.
Regarding the limitation the second nucleic acid portion of (b) and the said 1-8 additional nucleic acid portions are linked to selected passenger nucleic acid portions as respective primary structures, the Spec. doesn’t disclose what structure determines that a passenger nucleic acid is selected to have the 1-8 additional nucleic acid portions linked to it, and the Spec. doesn’t disclose any requisite structure responsible for the linking.
Regarding the further pharmaceutically active agents, the Spec. doesn’t disclose any structure responsible for an agent’s pharmaceutical activity.
Regarding the limitation …an RNAi agent which is directed to a different target from PCSK9 and from APOC3; and/or wherein said agent(s) comprise a lipid-lowering agent…, the Spec. doesn’t disclose any structure that is required to be an RNAi agent which is directed to a different target from PCSK9 and from APOC3 or to be a lipid-lowering agent.
A person of ordinary skill knows there are numerous target genes and each of them comprises a different structure that underlies its functions. Even APOC3 and PCSK9 mRNA are >500 to >3500 bp long (see NCBI. Homo sapiens apolipoprotein C3 [APOC3], mRNA and Homo sapiens proprotein convertase subtilisin/kexin type 9 [PCSK9], transcript variant 1, mRNA. Available online at ncbi.nlm.nih.gov. Accessed on 21 May 2026, “NCBI”). The claims encompass any portions of or complementary to any of them without providing detail about what constitutes a suitable portion. While the claims encompass all of them, it’s not clear that Applicant was in possession of a representative number.
Regarding what structures are encompassed by the first/second/third/fourth, and 1-8 additional nucleic acid portions that are at least partially complementary to portions of RNA transcribed from a target gene; the first/second or 1-8 portions of an RNA which is transcribed from a PCSK9/APOC3/any other target gene; the nucleic acid portions that form duplex regions or additional duplex regions with first/second nucleic acid portions or additional 1-8 nucleic acid portions…; the 1 to 8 additional nucleic acid portions that are respectively at least partially complementary to an additional 1 to 8 portions of RNA transcribed from one or more target genes, wherein each of the 1 to 8 additional nucleic acid portions respectively forms additional duplex regions with respective passenger nucleic acid portions; the portions that that respectively form additional duplex regions with respective passenger nucleic acid portions or that form respective passenger nucleic acid portions; the further pharmaceutically active agents and the RNAi agents directed to targets other than PCSK9/APOC3 and the lipid-lowering agents; and the structure that is responsible for the construct being cleaved so as to yield discrete nucleic acid targeting molecules; portions that are cleaved to yield discrete nucleic acid-targeting molecules, the linker modalities that link nucleic acids as a primary structure or respective primary structure, and the other characteristics discussed above, the Spec. does not provide information describing their features.
The Spec. does not disclose what physical structures are responsible for the claimed functions of being a portion that is at least partially complementary to a portion of an RNA transcribed from PCSK9/APOC3/any other target gene; comprising a portion of a transcribed RNA; characteristics of nucleic acid portions that form complementarity with other nucleic acid portions, forming duplex regions or additional duplex regions, or being passenger nucleic acid portions; being cleaved so as to yield discrete nucleic acid-targeting molecules; linking nucleic acids so as to for a primary or respective primary structure; being an RNAi agent for a different gene; or lowering lipids.
Applicant’s examples show siRNA agents that target PCSK9 and APOC3. However, those examples are not sufficient to provide written description support for possession of the genera encompassed by the claims (i.e., the first/second/third/fourth, and 1-8 additional nucleic acid portions that are at least partially complementary to portions of RNA transcribed from a target gene; the first/second or 1-8 portions of an RNA which is transcribed from a PCSK9/APOC3/any other target gene; the nucleic acid portions that form duplex regions or additional duplex regions with first/second nucleic acid portions or additional 1-8 nucleic acid portions…; the 1 to 8 additional nucleic acid portions that are respectively at least partially complementary to an additional 1 to 8 portions of RNA transcribed from one or more target genes, wherein each of the 1 to 8 additional nucleic acid portions respectively forms additional duplex regions with respective passenger nucleic acid portions; the portions that that respectively form additional duplex regions with respective passenger nucleic acid portions or that form respective passenger nucleic acid portions; the further pharmaceutically active agents and the RNAi agents directed to targets other than PCSK9/APOC3 and the lipid-lowering agents; and the structure that is responsible for the construct being cleaved so as to yield discrete nucleic acid targeting molecules; portions that are cleaved to yield discrete nucleic acid-targeting molecules, the linker modalities that link nucleic acids as a primary structure or respective primary structure, and the other characteristics discussed above). Although the claims claim the functional characteristics (i.e., lowering lipids, inhibiting any target gene, being a nucleic acid portion that is partially complementary to at least a portion of RNA transcribed from a gene, being a portion of RNA transcribed from a gene, being cleaved so as to yield at least first and second discrete nucleic acid-targeting molecules, being a selected passenger nucleic acid portion, linking nucleic acids so as to form primary structures, etc.), the functional characteristics are not coupled with any known structure.
Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for performing the claimed function(s) discussed above. The Spec. does not disclose any core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for the functions in such a way to demonstrate possession of the full invention as claimed at time of filing.
The specification teaches only some species within the claimed genus/genera (i.e., the SEQ ID NOs listed in the Spec. and the optional lipid-lowering agents recited by name in Claim 26) but those are only a paltry number compared with the breadth of what is claimed. Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genera and subgenera that are encompassed by the claims.
While none of these elements is specifically required to demonstrate possession, in combination their absence means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of the full breadth of the invention claimed. Claims 1-8, 11-16, 20, and 25-26 are rejected for failing to demonstrate possession of the claimed invention. Claims 2-26 are rejected because they depend from Claim(s) 1-8, 11-16, 20, and/or 25-26 and do not remedy the issues.
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 1-26 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.
NOTE: these rejections are organized under subheadings as a courtesy. The headings are general and other kinds of indefinite rejection can appear in each §.
Indefinite metes and bounds
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173. In the present instance, Claims 1-26 recite or depend from a claim reciting various portion(s).
The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim because it isn’t clear what is a portion. An artisan wouldn’t know what constitutes a nucleic acid portion, a portion of an RNA which is transcribed from a gene, a portion that is at least partially complementary to another portion which itself is a portion, a passenger portion, a linker portion, or any other recited portion. A portion isn’t a term of the art or defined in the Spec.
Claims 1-9, 11-16, and 20 are rejected for those reasons. Claims 2-26 are rejected because they depend from Claims 1-9, 11-16, and/or 20 and don’t remedy the issues. In the interest of compact prosecution the claims are interpreted as requiring the portions are interpreted as strands of a dsRNA or a linker.
In the present instance, Claims 3, 5, and 8 recite as a primary structure or as respective primary structure.
The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim because it isn’t clear what is a primary structure or a respective primary structure or what is meant by a primary structure or a respective primary structure. That isn’t a term of the art or defined in the Spec.
Claims 3, 5, and 8 are rejected for those reasons. Claims 9-10 are rejected because they depend from Claim 3 and don’t remedy the issues. In the interest of compact prosecution the claims are interpreted as requiring the nucleic acids are linked and the limitation about any primary structure is not considered.
In the present instance, Claim 9 recites said linking represents.
The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim because it isn’t clear what is meant by represents. That isn’t a term of the art or defined in the Spec. The term “represents” in claim 9 is a relative term which renders the claim indefinite. The term “represents” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. A person of ordinary skill wouldn’t know whether (i)-(iii) adequately “represents” the linking.
In addition, there is unclear antecedent basis for this limitation in the claims because none of the claims it depends from recites any linking. Claim 3 recites that some of the nucleic acid portions are linked, but there are also inter-nt linkages. Therefore it’s not clear to which of the linkages said linking refers.
Furthermore, Claim 9 is unclear because it recites …said linking represents either (i)… (ii) an inter-nt nick… but it’s not clear how a linkage (which by its plain meaning indicates two things are connected) can also be a nick which is the absence of something. It is unclear how the absence of a connection serves as any sort of connection.
Claim 9 is rejected for those reasons. Claim 10 is rejected because it depends from Claim 9 and doesn’t remedy the issues. In the interest of compact prosecution the claims are interpreted as referring to a linker that links strands of (a) and (d). The limitation about the nick is not examined due to the lack of clarity in the claims.
NOTE: any new rejection required by any amendment that reconciles the lack of clarity over how an inter-nt nick links (a) and (d) will not preclude the next Office Action from being final.
In the present instance, Claim 10 recites said inter-nt bond involves… position of (at least one of) said unmodified nt.
The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim because it isn’t clear what is meant by involves. That isn’t a term of the art or defined in the Spec. and whether or not something is involved in something else depends on the eye of the beholder. In addition, it is not clear why the one recitation is in parentheses. Does that mean it need not be considered for the claim?
Claim 10 is rejected for those reasons. In the interest of compact prosecution the claims are interpreted as requiring that the inter-nt bond links one of the unmodified nt to another nt (which can be modified or unmodified). Amending the claim to remove the parentheses will obviate the other part of this rejection and in the interest of compact prosecution, the claim is interpreted as if it requires that the optional cleavage occurs at the 3’ side of an unmodified nt.
In the present instance, Claim 16 recites to the extent present, the nucleic acid linker portion.
The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim because it isn’t clear what is meant by to the extent present. Claim 16 depends from Claim 1 which recites that the two duplexes are joined by an unmodified nt. That unmodified nt serves, structurally, as a linker (see below §§Lack of or insufficient clear antecedent basis). Therefore it isn’t clear how the linker in Claim 16 might not be present.
Claim 16 is rejected for those reasons. In the interest of compact prosecution Claim 16 is interpreted as if it doesn’t recite to the extent present in front of the nucleic acid linker portion.
In the present instance, Claim 21 recites: The construct of claim 1, wherein said construct comprises two strands, wherein the first strand is SEQ ID NO. 78 and the second strand is SEQ ID NO. 132.
Claim 21 depends from Claim 1 which recites:
… the construct further comprises at least one labile functionality such that subsequent to in vivo administration said construct is cleaved so as to yield at least first and second discrete nucleic acid targeting molecules; and wherein said labile functionality comprises one or more unmodified nucleotides.
The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. The metes and bounds are unclear because examination of SEQ ID NOs 78 and 132 finds that they are both fully modified sequences.
Therefore it is unclear how the construct of Claim 21 can possess the structure and functionality recited in Claim 1: the construct further comprises at least one labile functionality such that subsequent to in vivo administration said construct is cleaved so as to yield at least first and second discrete nucleic acid targeting molecules; and wherein said labile functionality comprises one or more unmodified nucleotides.
Claim 21 is rejected for those reasons. Claim 22 is rejected because it depends from Claim 21 and doesn’t remedy the issues. In the interest of compact prosecution Claim 21 is interpreted as:
A nucleic acid construct comprising two strands, wherein the first strand is SEQ ID NO 78 and the second strand is SEQ ID NO 132.
In the present instance, Claim23 recites further comprising a physiologically acceptable excipient.
The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim because it isn’t clear what is a physiologically acceptable excipient. That isn’t a term of the art or defined in the Spec. and the metes and bounds of the term vary depending on the physiology of an individual because what is or is not a physiologically acceptable excipient for Person 1 may not be a physiologically acceptable excipient for Person 2.
Claim 23 is rejected for those reasons. Claims 24-26 are rejected because they depend from Claim 23 and don’t remedy the issues. In the interest of compact prosecution the claims are interpreted as requiring a pharmaceutically acceptable excipient. Amending the claim in that way, as/if appropriate, will obviate this rejection.
Lack of or insufficient clear antecedent basis
Claims 7-8, 13, 15-16 recite the limitations: "passenger nucleic acid portions" or "said passenger nucleic acid portions" in L4 (Claim 7), L2 (Claim 8), L10 (Claim 13), L8 (Claim 15), and L8 (Claim 16). There is insufficient antecedent basis for this limitation in the claims because none of the claims they depend from recite any passenger nucleic acid portions.
In addition, Claim 8 recites selected passenger nucleic acid portions but nothing in the other claims provides antecedent basis for the selection.
Claims 7-8, 13, 15-16 are rejected for those reasons and Claims 14-15 and 17-19 are rejected because they depend from Claims 7-8, 13, 15-16 and don’t remedy the issues. In the interest of compact prosecution the passenger nucleic acid portion is interpreted as the nucleic acid that base pairs (forms a complementary strand) with the nucleic acid that is at least partially complementary to the target RNA. The limitation in Claim 8 selected is interpreted as meaning whatever strand is linked to (b).
Claim 12 recites …wherein said unmodified nt …. There is insufficient antecedent basis for the limitation said unmodified nt in the claim because neither Claim 12 nor any of the claims on which it depends recites any said unmodified nt. Claim 1 recites a labile functionality comprising one or more unmodified nt but those are clearly not the same said unmodified nt that is recited in Claim 12 because the labile functionality comprising one or more unmodified nt is further to the first/second/third/fourth nucleic acid portions whereas the said unmodified nt that is recited in Claim 12 is or can be located within the first/second/third/fourth nucleic acid portions.
Claim 12 is rejected for those reasons. Claims 13-15 are rejected because they depend from Claim 12 and don’t remedy the issues. In the interest of compact prosecution the claims are interpreted as requiring that the nt at any of recited positions 18-25 is unmodified.
Claims 13-16 recite the limitation "nucleic acid linker portion" in L1 and L7-10 (Claim 13), L3-4 (Claim 14), L3-8 (Claim 15), and L3-9 (Claim 16). There is insufficient antecedent basis for this limitation in the claim because none of the claims from which Claims 13-16 depend recite a nucleic acid linker portion or a clear antecedent basis for the limitation.
Claims 13-16 are rejected for those reasons. Claims 14-16 are rejected because they depend from Claims 13-16 and don’t remedy the issues. In the interest of compact prosecution, the nucleic acid linker portion is interpreted to be the one labile functionality that comprises one or more unmodified nt recited in Claim 1.
Claim 13 recites …one or more of the 5’ and/or 3’ regions of said…. There is insufficient antecedent basis for the limitation the 5’ and/or 3’ regions in the claim because neither Claim 13 nor any of the claims on which it depends recites an 5’ and/or 3’ region. Although any nucleotide or oligonucleotide comprises 5’- and 3’-terminal ends, what is meant by the 5’ and/or 3’ regions is unclear because what constitutes a 5’ and/or 3’ region is not defined.
Claim 13 is rejected for those reasons. Claims 14-15 are rejected because they depend from Claim 13 and don’t remedy the issues. In the interest of compact prosecution the claims are interpreted as requiring that the inter-nt linkage is located anywhere within the oligonucleotide.
Relative term or broad/narrow
The term “selected” in Claim 8 is a relative term which renders the claim indefinite. The term “selected” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree of what makes something selected or not selected, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. A person of ordinary skill wouldn’t know whether a passenger nucleic acid portion was selected or not.
In the interest of compact prosecution the term selected is interpreted as referring to a nucleic acid that is complementary to a nucleic acid that is complementary to the target RNA.
A broad limitation together with a narrow limitation that falls within the broad 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, Claims 11-13 recite the broad recitations about nucleic acid portion length (Claim 11), the locations of unmodified nt (Claim 12), and nucleic acid linker portion length (Claim 13), and the claim also recites narrower ranges for nucleic acid portion length, a shorter list of unmodified nt positions, and narrower ranges of nucleic acid linker length, which are the narrower statements of the limitations. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 11-13 are rejected for those reasons. Claims 12-15 are rejected because they depend from Claims 11-13 and don’t remedy the issues. In the interest of compact prosecution the full range of the recited limitation is considered acceptable and the narrower ranges are considered exemplary.
In the present instance, Claim 18 recites the broad recitation nucleotides with 2’ modified sugars, and the claim also recites wherein optionally said 2' modified sugar is selected from 2'-O-alkyl modified sugar, 2'-O-methyl modified sugar, 2'-O-methoxyethyl modified sugar, 2'-O-allyl modified sugar, 2'-C-allyl modified sugar, 2'-deoxy modified sugar such as 2'-deoxy ribose, 2'-F modified sugar, 2'-arabino-fluoro modified sugar, 2'-O-benzyl modified sugar, 2'-amino modified sugar, and 2'-O-methyl-4-pyridine modified sugar which is the narrower statement of the limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the interest of compact prosecution the optional species of 2’ modified sugar are interpreted as fully optional and not required.
In the present instance, Claim 26 recites the broad recitation a lipid-lowering agent, and the claim also recites wherein said lipid-lowering agent is optionally is ezetimib which is the narrower statement of the limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the interest of compact prosecution the optional species of lipid-lowering agent are interpreted as fully optional and not required.
“Such as”
Regarding Claims 18 and 26, the phrase "such as" or “such [as]” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
In the interest of compact prosecution the phrases that come after “such as” are interpreted as exemplary and not required.
Tradenames
Claim 26 contains the trademark/trade name Vascepa®.
Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe icosapent ethyl and, accordingly, the identification/description is indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 21 and 22 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 21 recites: The construct of claim 1, wherein said construct comprises two strands, wherein the first strand is SEQ ID Nos. 78 and the second strand the group consisting of SEQ ID Nos. 132. Examination of those SEQ ID NOs finds that they are both fully modified sequences.
Yet, Claim 21 depends from Claim 1 which recites:
… the construct further comprises at least one labile functionality such that subsequent to in vivo administration said construct is cleaved so as to yield at least first and second discrete nucleic acid targeting molecules; and wherein said labile functionality comprises one or more unmodified nucleotides.
As discussed in §112b above, it is not clear how, even if the labile functionality were to connect the terminal ends of the strands, the construct could be cleaved to yield at least first and second discrete nucleic acid targeting molecules.
In addition, the Spec. indicates that the labile functionality that is cleaved so as to yield at least first and second discrete nucleic acid-targeting molecules and which comprises one or more unmodified nt is absent from SEQ ID NOs 78 and 132. The text ahead of the tables discloses (Spec. p. 41 L4-5 and p. 47): Table 5a[/5b] shows linked first and fourth [/second and third] nucleic acid portions of the molecules. Linking is direct to give rise to a single contiguous strand.
Therefore Claim 21 fails to include the limitation wherein said labile functionality comprises one or more unmodified nucleotides of Claim 1 and is rejected for that reason.
Claim 22 is rejected because it depends from Claim 21 and doesn’t remedy the issues.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3, 7-19, and 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over International Patent Application Publication No. WO 2020/065602 (published 02 April 2020, “WO602”, of record on IDS) and Ruotsalainen (et al. 19 June 2021. Novel RNAi-Based Therapies for Atherosclerosis. Curr. Atheroscler. Report 23:45, “Ruotsalainen”).
NOTE: references to p. # in WO documents refer to PDF p. #.
WO602 is drawn to (§Abstract) products and composition for:
a multi-targeting nucleic acid construct comprising at least:
(a) a first nucleic acid portion that is at least partially complementary to at least a first portion of RNA transcribed from a target gene;
(b) a second nucleic acid portion that is at least partially complementary to at least a second portion of RNA transcribed from a target gene, which target gene may be the same or different to the target gene defined in (a);
(c) a third nucleic acid portion that is at least partially complementary to the first nucleic acid portion of (a), so as to form a first nucleic acid duplex region therewith;
(d) a fourth nucleic acid portion that is at least partially complementary to said second nucleic acid portion of (b), so as to form a second nucleic acid duplex region therewith;
[wherein] the construct is designed so that subsequent to in vivo administration the construct disassembles to yield at least first and second discrete nucleic acid targeting molecules that respectively target RNA transcribed from the target genes of (a) and (b).
WO602 teaches (p. 5 L24-30) the labile functionality that, subsequent to in vivo administration, is cleaved so as to yield at least the first and second discrete nucleic acid targeting molecules and that the labile functionality can comprise one or more unmodified nt. WO602 teaches (same §) the labile functionality that links the two dsRNA can represent one or more cleavage position within the construct.
Therefore WO602 teaches all the limitations of Claim 1 besides for the two targets.
Regarding Claims 3 and 5: WO602 teaches (p. 6 L1-6) the nucleic acid of (a) can be directly or indirectly linked to (d) as a primary structure or the nucleic acid of (b) can be directly or indirectly linked to (c) as a primary structure. Therefore WO602 teaches limitations of Claims 3 and 5.
Regarding Claims 7-8: WO602 teaches (p. 6 L6-17) the additional 1-8 dsRNAs that form duplex regions, can be complementary to additional targets, and wherein the second nucleic acid portion of (b), and the 1 to 8 additional nucleic acid portions, are directly or indirectly linked to selected passenger nucleic acid portions as respective primary structures. Therefore WO602 teaches limitations of Claims 7-8.
Regarding Claim 9, WO602 teaches (p. 6 L19-25) the direct or indirect linking between the pieces of the construct can be …either (i) an internucleotide nick, (ii) an internucleotide bond, or (iii) a nucleic acid linker portion of 1 to 10 nucleotides… and (p. 7 L30-31) the nucleic acid linker portion can be single-stranded. Therefore WO602 teaches limitations of Claim 9.
Regarding Claim 10, portions of WO602 discussed above describe that WO602 teaches the labile functionality can comprise one or more unmodified nt and that the linking modality can be an inter-nt bond. Together, those teachings indicate that the inter-nt bond links the unmodified nt. Regarding the optional limitation of Claim 10, WO602 describes that (pp. 6-7 L19-31) the cleavage occurs at the 3’ position of at least one of the unmodified nt. If cleavage occurs between two nt (as the cited § teaches), it would have to occur at the 3’ end of one of those nt. Therefore WO602 teaches limitations of Claim 10.
Regarding Claim 11, WO602 teaches (p. 8 L24-29) the nucleic acid portions of (a)-(d) can be 7-20, 10-18, or 15 nt long and (p. 19 L10-20, Fig. 5) alternative embodiments wherein the nucleic acid portion lengths can be 20-50 nt long. Therefore WO602 teaches limitations of Claim 11.
Regarding Claim 12, WO602 teaches that (p. 9-13 L25-25) the nucleic acids within the construct (p. 13 L15-25) can be modified and the construct can also comprise one or more unmodified nt at any of the positions in the construct, including portions of the linker that are adjacent to (c). Further, Figs. 2-3 show (pp. 46-47, pp. 17-18 L30-26) constructs comprising unmodified nt (stars) at terminal positions. If the nucleic acids of (a)-(d) are 18- to 25-mer (well within the lengths specified, i.e., 7-20 or 20-50 nt), unmodified nt at terminal positions would be placed at positions 18-25. Therefore WO602 teaches limitations of Claim 12.
Regarding Claim 13, WO602 teaches (p. 8 L29-30) the nucleic acid linker can be 1-8 nt long, 2-6 nt long, or 4 nt long. WO602 teaches (p. 8 L31-37) the construct can comprise one or more phosphorothioate (PS) or phosphorodithioate (P2S) linkages and that they are located at one or more of the 5’ and/or 3’ regions of (a)-(d), and/or the 1-8 additional nucleic acid portions, and/or the passenger nucleic acid portions. Therefore WO602 teaches limitations of Claim 13.
Regarding Claims 14-15, WO602 teaches (p. 9 L4-24) the PS or P2S inter-nt linkage is between at least two adjacent nt of the linker portion or between each adjacent nt of the linker. WO602 teaches (same §) the construct comprises a PS or P2S inter-nt linkage linking any of (a), (b), (c), and/or (d), and/or the 1-8 additional nucleic acid portions, and/or the passenger nucleic acid portions to the nucleic acid linker portion. Therefore WO602 teaches limitations of Claims 14-15.
Regarding Claim 16, WO602 teaches (pp. 9-10 L25-4) at least one nt of the following is modified: (a)-(d), the 1-8 additional nucleic acid portions, the passenger nucleic acid portions, and/or the nucleic acid linker portion. Therefore WO602 teaches limitations of Claim 16.
Regarding Claims 17-19, WO602 teaches (pp. 12-13 L18-16) the construct comprises modifications that can be sugar, backbone, or base modifications, wherein the sugar modifications can be 2’-OMe and/or 2’-F. Therefore WO602 teaches limitations of Claims 17-19.
Regarding some limitations of Claims 20-22, namely the alternating 2’-OMe–2’-F modification pattern and the 5’-terminal phosphate, WO602 teaches (pp. 10-12 L5-16) modification patterns wherein odd numbered nt have one modification and even numbered nt have a different modification. Furthermore, WO602 shows (Table 3, starts on p. 25) nucleic acid strands comprising an alternating 2’-OMe–2’-F modification pattern and a 5’-phosphate. Therefore WO602 teaches the alternating modification patterns of the SEQ ID NOs recited in Claims 20-22.
Regarding Claims 23-24, WO602 teaches (p. 15 L15-25) using the construct to treat a disease or disorder and compositions comprising the construct and a physiologically acceptable excipient. Therefore it is clear WO602 intended their composition for use in a pharmaceutical composition, thereby teaching the limitations of Claim 23. Since that § is silent to any other active agent, WO602 teaches the limitations of Claim 24.
WO602 does not teach (a) is at least partially complementary to an RNA that is transcribed from a PCSK9 gene or that (b) is at least partially complementary to an RNA that is transcribed from a APOC3 gene.
However, Ruotsalainen teaches RNAi-based therapies for atherosclerosis. Ruotsalainen teaches (§Introduction ¶1) in RNAi, complementary double-stranded RNA molecules (dsRNA or siRNA) cleave a specific sequence of the target mRNA.
Regarding the specific targets PCSK9 and APOC3, Ruotsalainen teaches (§PCSK9 ¶1, Table 1) an FDA-approved siRNA therapy that targets and decreases expression of PCSK9. Ruotsalainen further teaches (§ApoCIII ¶1-3, Table 1) siRNA therapy that targets and decreases expression of APOC3.
Regarding Claims 25-26, Ruotsalainen teaches (§Advantages and Challenges of RNAi-Based Therapeutics in Lipid Lowering) double and triple combination therapies for cardiovascular diseases (CVD), including those combination therapies comprising statins. Ruotsalainen teaches (same §):
targeting different pathways of lipid metabolism and atherogenesis, like inflammatory pathways, may give great benefit in the reduction of CVD risk. Interestingly, the triple combination of alirocumab and evinacumab with statin treatment in hyperlipidemic mouse model, showed great reduction in plasma TG, total cholesterol, and non-HDL-C in comparison to single therapies [43]. This study also showed the total inhibition of atherogenesis, regression of atherosclerotic plaques, and even the beneficial effect on plaque morphology and stability in mouse model.
Altogether, Ruotsalainen teaches two separate dsRNAs:
a PCSK9-targeting dsRNA that comprises a portion that is at least that is at least partially complementary to PCSK9 mRNA (which is transcribed from a PCSK9 gene) and
a APOC3-targeting dsRNA that comprises a portion that is at least that is at least partially complementary to APOC3 mRNA (which is transcribed from an APOC3 gene).
That indicates that dsRNAs targeting PCSK9 and APOC3 were known in the art of treating CVD. Ruotsalainen also teaches benefits of combination therapies, including a triple combination comprising a statin, for treating CVD. Therefore Ruotsalainen teaches limitations of Claims 1 and 25-26.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the nucleic acid construct of WO602 with the PCSK9-targeting dsRNA and APOC3-targeting dsRNA of Ruotsalainen for the benefit of treating CVD by modulating two different pathways. One would have been motivated to do so with a reasonable expectation of success because WO602 teaches that their multi-targeting construct can target any two genes and Ruotsalainen teaches using combination therapies to treat CVD provides great improvements to patients. One would have been motivated to do so with a reasonable expectation of success because WO602 teaches (p. 4 L23-30) their invention:
address[es] and improv[es] shortcomings associated with the complementary oligonucleotide technologies (e.g. antisense and RNAi technologies), such as high cost of production, suboptimal efficacy and specificity, low stability of molecules in biological fluids and inside the cells, and difficulty of delivery in cell culture and in vivo
and an artisan would have wanted to apply those improvements to Ruotsalainen’s known dsRNA for treating CVD. It would have been a simple matter to reformat Ruotsalainen’s known dsRNA into the improved construct of WO602. Therefore the limitations of Claims 1, 3, 7-19, and 23-24 would have been obvious in view of WO602 and Ruotsalainen.
It would have been further obvious to add the statin for treating CVD of Ruotsalainen to the pharmaceutical composition comprising the PCSK9- and APOC3-targeting nucleic acid construct of WO602 and Ruotsalainen for the benefit of further treating CVD in patients taking statins. One would have been motivated to do so with a reasonable expectation of success because Ruotsalainen teaches many statin treated patients reach improved efficiency on plasma lipid lowering with PCSK9 inhibition. It would have been a simple matter to add the readily available statin of Ruotsalainen to the pharmaceutical composition of WO602 and Ruotsalainen. Therefore the limitations of Claims 25-26 would have been obvious in view of WO602 and Ruotsalainen.
Claim(s) 1-26 are rejected under 35 U.S.C. 103 as being unpatentable over WO602 and Ruotsalainen as applied to Claims 1, 3, 7-19, and 23-26 above, and further in view of International Patent Application Publication No. WO 2008/109472 (published 12 September 2008, “WO472”), International Patent Application Publication No. WO 2010/083615 (published 29 July 2010, “WO615”), and Kamola (et al. 2015. The siRNA Non-seed Region and Its Target Sequences Are Auxiliary Determinants of Off-Target Effects. PLoS Comput. Biol 11[12]:e1004656, “Kamola”).
The teachings of WO602 and Ruotsalainen as applicable to Claim(s) 1, 3, 7-19, and 23-26 have been described above.
WO602 and Ruotsalainen make obvious the construct recited in instant Claim 1.
WO602 and Ruotsalainen do not teach the claimed SEQ ID NOs.
However, those sequences would have been obvious in view of the prior art.
Regarding the PCSK9-targeting oligont, WO472, drawn to nicked/gapped dsRNA, teaches (pp. 4-5 L20-14) first strands that are complementary to PCSK9 mRNA as set forth in SEQ ID NO 1158. WO472 teaches (same §) the second and third strands are complementary to the first strand, can each be 5-20 nt long, and their combined length can be 15 nt long. WO472 teaches (p. 82 item 20) the first strand can be 19-23 nt long and complementary to a human PCSK9 nucleic acid sequence, a target sequence as set forth in SEQ ID NO 1355. SEQ ID NO 1355 is a 19-mer and 94.7% complementary to claimed SEQ ID NO 4 as shown by the following alignment:
ATN17917/c
(NOTE: this sequence has 2 duplicates in the database searched.
See complete list at the end of this report)
ID ATN17917 standard; mRNA; 19 BP.
XX
AC ATN17917;
XX
DT 13-NOV-2008 (first entry)
XX
DE Human PCSK9 mRNA target sequence for mdRNA, SEQ ID:1355.
XX
KW ss; RNA interference; gene silencing; gene regulation; gene therapy;
KW diagnostic test; therapeutic; prophylactic to disease; drug discovery;
KW multidrug resistance; atherosclerosis; antiarteriosclerotic; antilipemic;
KW metabolic-gen.; diabetes mellitus; antidiabetic; gastrointestinal-gen.;
KW cardiovascular disease; cardiovascular-gen.; cerebrovascular ischemia;
KW cerebroprotective; vasotropic; lipid metabolism disorder;
KW cerebrovascular disease; brain hemorrhage; hemostatic;
KW influenza virus infection; respiratory-gen.; virucide;
KW proprotein convertase subtilisin-like kexin 9; PCSK9.
XX
OS Homo sapiens.
XX
CC PN WO2008109472-A2.
XX
CC PD 12-SEP-2008.
XX
CC PF 29-FEB-2008; 2008WO-US055554.
XX
PR 02-MAR-2007; 2007US-0934940P.
PR 16-MAR-2007; 2007US-0934930P.
XX
CC PA (NAST-) NASTECH PHARM CO INC.
XX
CC PI Quay SC, Mcswiggen J, Vaish NK, Ahmadian M;
XX
DR WPI; 2008-M01608/70.
XX
CC PT New meroduplex ribonucleic acid for treating e.g. stroke comprises three
CC PT strand combine to form two non-overlapping double-stranded regions
CC PT separated by gap, where one strand is complementary to proprotein
CC PT convertase subtilisin-like kexin 9.
XX
CC PS Claim 20; SEQ ID NO 1355; 95pp; English.
XX
CC The present invention relates to a novel meroduplex ribonucleic acid
CC (mdRNA) molecule, having a nick or gap in at least one strand, which is
CC useful for treating proprotein convertase subtilisin-like kexin type 9
CC (PCSK9) related diseases or disorders e.g. cancer. The mdRNA molecule
CC comprises at least three strands, where the first strand is 15-40
CC nucleotides in length, and is complementary to a portion of human PCSK9
CC messenger RNA (mRNA); the second and third strands are each complementary
CC to non-overlapping regions of the first strand, and can anneal with first
CC strand to form at least two double-stranded regions spaced apart by up to
CC 10 nucleotides to form a gap between the second and the third strands.
CC The term "mdRNA" as used herein, is interchangeable with "dsRNA," which
CC refers to any nucleic acid molecule comprising at least one
CC ribonucleotide molecule capable of inhibiting or down regulating gene
CC expression, for example, by promoting RNA interference ("RNAi") or gene
CC silencing in a sequence-specific manner. The mdRNA/dsRNA/Dicer substrate
CC or the short interfering RNA (siRNA) of the invention is useful in
CC silencing the gene activity of each of the 22 target genes namely, v-akt
CC murine thymoma viral oncogene homolog 1 (AKT1), epidermal growth factor
CC receptor (EGFR), FMS-related tyrosine kinase 1 (FLT1), FKBP12-rapamycin
CC complex-associated protein 1 (FRAP1), hypoxia-inducible factor 1, alpha
CC subunit (HIF1A), interleukin 17a (IL17A), interleukin 18 (IL18),
CC interleukin 6 (IL6), mitogen-activated protein kinase kinase 1 (MAP2K1),
CC mitogen-activated protein kinase 1 (MAPK1), mitogen-activated protein
CC kinase 14 (MAPK14), platelet-derived growth factor, alpha polypeptide
CC (PDGFA), platelet-derived growth factor receptor, alpha (PDGFRA),
CC phosphatidylinositol 3-kinase, catalytic, alpha (PIK3CA), protein kinase
CC n3 (PKN3), v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1),
CC steroid 5-alpha-reductase 1 (SRD5A1), tumor necrosis factor (TNF), tumor
CC necrosis factor ligand superfamily, member 13b (TNFSF13B), vascular
CC endothelial growth factor A (VEGFA), BCR-ABL [b2a2], and BCR-ABL [b3a2].
CC The invention is useful for silencing the expression of human PCSK9 gene;
CC for manufacturing a medicament for treating atherosclerosis, diabetes
CC mellitus, cardiovascular disease, cerebrovascular ischemia, lipid
CC metabolism disorder, cerebrovascular disease, brain hemorrhage, and
CC influenza virus infection; and as therapeutic tools to regulate
CC expression of PCSK9. The invention is also useful in research and
CC diagnostic methods including scientific and commercial research
CC elucidation of physiological pathways, drug discovery and development,
CC and medical and veterinary diagnostics; and in target validation, genomic
CC discovery, genetic engineering, and pharmacogenomic applications. The
CC present sequence represents a human PCSK9 mRNA fragment which is
CC specifically claimed as a target for mdRNAs of the invention.
XX
SQ Sequence 19 BP; 2 A; 4 C; 3 G; 0 T; 10 U; 0 Other;
Query Match 94.7%; Score 18; Length 19;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 2 GCAAAACAGGTCTAGAAA 19 Claimed SEQ ID NO 4
||||||||||||||||||
Db 18 GCAAAACAGGTCTAGAAA 1 WO472 PCSK9 target sequence SEQ ID NO 1355
That alignment shows that WO472 teaches a sequence comprising all but the 5’-terminal U of claimed SEQ ID NO 4.
Although WO472 teaches gapped dsRNA comprising three strands, it teaches (pp. 12-14 L25-28) two-stranded dsRNA, that the terms dsRNA and mdRNA are interchangeable, and that both kinds of dsRNA associate with RISC to mediate gene silencing by RNAi.
WO472 teaches (p. 24 L30-35) the first strand can have 1-3 mismatches with PCSK9 mRNA. WO472 teaches (p. 6 L14-16) their dsRNA can be modified with 2’-OMe and 2’-F. WO472 teaches (p. 3 L8-15) their dsRNA are for treating CVD and dislipidemia.
Regarding the APOC3-targeting oligont, WO615, drawn to APOC3-targeting RNAi, teaches (¶12-13) modified dsRNA that target and silence APOC3 to reduce triglyceride and cholesterol levels in vivo. WO615 teaches (¶364) the sense strand comprises at least 15 contiguous nt of their disclosed sense strands and at least 15-19 contiguous nt of their disclosed AS strands. WO615 discloses (Table 7) two 19-mer AS strands (SEQ ID NOs 53 and 54) that each comprise 94.7% identity to claimed SEQ ID NO 10 as shown by the following alignment to WO615 SEQ ID NO 54:
AYE61844
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
ID AYE61844 standard; RNA; 19 BP.
XX
AC AYE61844;
XX
DT 16-SEP-2010 (first entry)
XX
DE Human APOC3 gene targeted siRNA antisense strand #54.
XX
KW APOC3 gene; Apolipoprotein C3; anorectic; antiarteriosclerotic;
KW antidiabetic; antiinflammatory; antilipemic; atherosclerosis; cardiant;
KW cardiovascular disease; cardiovascular-gen.; coronary artery disease;
KW diabetes mellitus; drug delivery; gastrointestinal-gen.; gene silencing;
KW hypercholesterolemia; hypertriglyceridemia; lipid metabolism disorder;
KW metabolic-gen.; nutrition-disorder-gen.; obesity; pancreatitis;
KW prophylactic to disease; rna interference; short interfering RNA; siRNA;
KW ss; steatosis; therapeutic; vasotropic.
XX
OS Homo sapiens.
XX
CC PN WO2010083615-A1.
XX
CC PD 29-JUL-2010.
XX
CC PF 26-JAN-2010; 2010WO-CA000120.
XX
PR 26-JAN-2009; 2009US-0147235P.
PR 08-JAN-2010; 2010US-0293452P.
XX
CC PA (PROT-) PROTIVA BIOTHERAPEUTICS INC.
XX
CC PI Lee ACH, Macdonald M, Maclachlan I;
XX
DR WPI; 2010-J73486/50.
XX
CC PT Composition useful for treating atherosclerosis, hypertriglyceridemia and
CC PT hypercholesterolemia, comprises small interfering RNA that silences
CC PT apolipoprotein C-III gene expression.
XX
CC PS Claim 9; Page 113; 159pp; English.
XX
CC The present invention provides a novel composition comprising a small
CC interfering RNA (siRNA) that silences apolipoprotein C-III (APOC3) gene
CC expression useful for treating atherosclerosis, hypertriglyceridemia and
CC hypercholesterolemia. The present invention also provides methods of
CC delivering and/or administering the lipid particles for the treatment of
CC lipid diseases or disorders. The present invention independently claims:
CC a nucleic acid-lipid particle comprising siRNA, cationic lipid and non-
CC cationic lipid; and a method for introducing siRNA that silences APOC3
CC gene expression into cell. The composition and nucleic acid-lipid
CC particle of the present invention are useful for preventing, treating,
CC ameliorating and/or delaying the onset of atherosclerosis or dyslipidemia
CC (such as hypertriglyceridemia and hypercholesterolemia), coronary heart
CC disease, coronary artery disease, fatty liver disease, pancreatitis,
CC diabetes, obesity and cardiovascular disease in humans. The composition
CC and nucleic acid-lipid particle of the present invention are so
CC beneficial as they have high solubility, bioavailability, biological half
CC -life, and shelf life. The present sequence is a human APOC3 gene
CC targeted siRNA antisense strand, which silences the apolipoprotein C-III
CC (APOC3) gene expression and is useful in a method for treating
CC atherosclerosis, hypertriglyceridemia and hypercholesterolemia as
CC described in the present invention.
XX
SQ Sequence 19 BP; 7 A; 5 C; 6 G; 0 T; 1 U; 0 Other;
Query Match 94.7%; Score 18; Length 19;
Best Local Similarity 94.4%;
Matches 17; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 2 CAACAAGGAGTACCCGGG 19 SEQ ID NO 10
||||||||||:|||||||
Db 2 CAACAAGGAGUACCCGGG 19 WO615 AS strand SEQ ID NO 54
That alignment shows that WO615 teaches a sequence comprising all but the 5’-terminal U of claimed SEQ ID NO 10.
WO615 teaches (¶40) their RNAi may comprise a mismatch to the target mRNA. WO615 teaches (¶163) modified nt including 2’-OMe and 2’-F. WO615 teaches (¶191) alternating 2’-OMe modifications. WO615 teaches (§Abstract) their dsRNA are for treating lipid diseases including hypercholesterolemia and dyslipidemia.
All of the WO472 and WO615 SEQ ID NOs referenced above are 100% complementary or identical to the target mRNA, and both WO472 and WO615 teach their dsRNAs can comprise a mismatch to their target mRNA.
WO602, Ruotsalainen, WO472, and WO615 do not AS strands wherein the 5’ nt is a U mismatch to the target mRNA.
However, Kamola, drawn to principles of rational sequence design for siRNAs, teaches benefits of producing siRNAs that comprise A/U at the 5’end of the guide strands (a person of ordinary skill understands that the terms “first strand”, “guide strand”, and “antisense strand” are synonymous). Kamola teaches (§Discussion ¶2) using A/U at the 5’end of the guide strand is one of the most widely accepted design algorithms of functional siRNAs for on-target repression because this placement produces asymmetrical thermodynamics of the two 5’ends wherein the strand with lower base-pairing stability at its 5’end is preferentially incorporated and retained in the RISC. Kamola further teaches (same §) A/U at the guide strand 5’terminal [end] shows the 30-fold higher affinity for anchoring in the Ago pocket compare to G/C. Kamola’s teachings indicate it was routine and conventional to produce siRNAs that comprise A/U at the 5’end of the guide strand because placing A/U at the 5’end of the guide strand makes it more likely that the guide strand is preferentially incorporated and retained in the RISC and because the 5’terminus has high affinity for anchoring in the Ago pocket.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the PCSK9- and APOC3-targeting nucleic acid construct of WO602 and Ruotsalainen with the AS strand sequences of WO472 and WO615 and the teachings of Kamola for the benefit using specific dsRNA sequences (which aren’t disclosed in Ruotsalainen) and optimizing the PCSK9- and APOC3-targeting construct of WO602 and Ruotsalainen. One would have been motivated to do so with a reasonable expectation of success because WO472 and WO615 respectively teach PCSK9- and APOC3-targeting dsRNA and an artisan would have used any of the sequences disclosed therein, including SEQ ID NO 1355 (WO472, PCSK9) and SEQ ID NOs 53-54 (WO615, APOC3) to inhibit expression of those targets. One would have been motivated to apply Kamola’s teachings about placing an A/U nt at the 5’-terminus of the guide strand for the benefits of producing 5’ends with asymmetrical thermodynamics so the guide strand is preferentially incorporated and retained in the RISC and improving affinity for anchoring the correct (i.e., guide) strand in the Ago pocket.
The teachings of Kamola would have motivated the artisan to replace the 5’terminal nt of the WO472 and WO615 SEQ ID NOs with an A/U nt. They would have tried both options (i.e., sequences with 5’terminal A and sequences with 5’terminal U) to determine whether either provides a better silencing outcome. Upon swapping out the 5’terminal nt of WO472 SEQ ID NO 1355 and WO615 SEQ ID NO 54 with U, they would have produced the sequences of claimed SEQ ID NOs 4 and 10.
It would have been obvious to then produce respective sense strands that base pair to the AS strands that would have been obvious in view of WO602, Ruotsalainen, WO472, WO615, and Kamola. An artisan would have tested a variety of sense strands and they would have been motivated to shorten those sense strands so as to save money by using fewer nt. Furthermore, 15-mer sense strands are well within the scope of what was routine and conventional in the art: all of WO602, WO472, and WO615 teach oligont segments or strands can vary in length, including lengths of 15-mer. Furthermore, both WO472 (p. 27, full ¶2) and WO615 (¶16) teach overhangs of 1-4 nt indicating longer AS strand were routine and conventional.
Producing sense strands to complement the AS strands of WO602, Ruotsalainen, WO472, WO615, and Kamola would have produced the sense strands of claimed SEQ ID NOs 18 and 24 and, therefore all the limitations of Claims 2 and 4-6 (and Claims 1, 3, 7-19, and 23-26).
Applying the known modification patterns of WO602 would have produced the limitations of Claim 20.
Regarding Claims 21-22, WO602 teaches (pp. 6-7 L25-29; pp. 17-19 L30-35; Figs. 2-3) various schemes comprising (p. 18 L10-26):
[multi-unit oligonucleotide nano-structures wherein] segments (1) and (4), as well as (2) and (3) are not physically (covalently) tied to each other. Thus the nano-structure is composed of four different oligo-nucleotide components. There is also partial complementarily between segments (1) and (3), in this case, also highlighted with stars (5). In case when segments (1), (2), (3) and (4) are chemically modified (e.g. by 2’F, 2”)Me, LNA modifications to increase stability against nucleases, stars (5) represent segments with “liable” positions (e.g. unmodified RNA or DNA nucleotides). In this particular case, the targeting/delivery moiety (6) (e.g. GaINAc, Cholesterol, etc) is attached (optionally) to different parts of the segments (2) and (4). The nano-structure depicted on the upper panel of the Figure 3 is synthesized and assembled in vitro (in the tubes). Upon introduction into biological environment (exposure to extra- and/or intra-cellular biological fluids), the “liable” nucleotides are cleaved and the nano-structure disassembles into the functional gene expression modulating agents (e.g. siRNAs). In this particular case, two separate different siRNAs are generated (lower part of the Figure 3). The passenger strands in such siRNAs would be somewhat shorter (could be as short as 8 nucleotides) than passenger strands in conventional siRNAs (18-21 nucleotides).
Note that the GalNAc targeting moiety is optional. A modified excerpt of Fig. 3 is shown here:
PNG
media_image1.png
333
418
media_image1.png
Greyscale
Furthermore, WO472 teaches gapped dsRNA wherein an AS strand simultaneously base pairs to two sense strands.
Configuring the nucleic acid construct that would have been obvious in view of WO602, Ruotsalainen, WO472, WO615, and Kamola in the scheme of WO602 shown in Fig. 3 would have produced Claimed SEQ ID NOs 78 and 132.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the oligont construct of WO602, Ruotsalainen, WO472, WO615, and Kamola with the construct design scheme of WO602 and teachings about a gapped nt of WO472 for the benefit of producing a multi-targeting nucleic acid construct while addressing and improving upon shortcomings associated with the complementary oligonucleotide technologies (e.g. antisense and RNAi technologies), such as high cost of production, suboptimal efficacy and specificity, low stability of molecules in biological fluids and inside the cells, and difficulty of delivery in cell culture and in vivo. One would have been motivated to do so with a reasonable expectation of success because WO602 teaches (p. 4 25-30) their design schemes provide those benefits and because WO472, WO615, and Kamola would have made obvious the nt sequences of claimed SEQ ID NOs 4, 10, 18, and 24. Then, it would have been obvious to produce claimed SEQ ID NOs 78 and 132 in view of the teachings of WO602. Therefore all the limitations of Claims 21-22 would have been obvious in view of WO602, Ruotsalainen, WO472, WO615, and Kamola.
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 1-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following claims of the following U.S. Patents in view of International Patent Application Publication No. WO 2020/065602 (published 02 April 2020, “WO602”, of record on IDS), Ruotsalainen (et al. 19 June 2021. Novel RNAi-Based Therapies for Atherosclerosis. Curr. Atheroscler. Report 23:45, “Ruotsalainen”), International Patent Application Publication No. WO 2008/109472 (published 12 September 2008, “WO472”), International Patent Application Publication No. WO 2010/083615 (published 29 July 2010, “WO615”), Kamola (et al. 2015. The siRNA Non-seed Region and Its Target Sequences Are Auxiliary Determinants of Off-Target Effects. PLoS Comput. Biol 11[12]:e1004656, “Kamola”), Vanio (et al. 2019. Connective Tissue Growth Factor Inhibition Enhances Cardiac Repair and Limits Fibrosis After Myocardial Infarction. JACC Basic Transl. Sci. 4[1]:83-94, “Vanio”), and Goumans (and ten Dijke. 2018. TGF-β Signaling in Control of Cardiovascular Function. Cold Spring Harb. Perspect. Biol. 10:a022210, “Goumans”).
NOTE: references to p. # in WO documents refer to PDF p. #.
Patent #
App. #
Claims
Additional notes
8664189
13/120315
all
Claims broadly recite treating a fibrotic disorder by inhibiting connective tissue growth factor (CTGF). An artisan might not know what that comprises so they’d look in the Spec. and find at ¶342 that the invention is for treating CVD.
9340786
13/636755
all
Claims broadly recite compounds that inhibit a gene encoding CTGF.
9642873
13/695073
all
Claim 29 recites treating the heart
9303259
14/104450
all
Claims broadly recite compounds that inhibit a gene encoding CTGF.
10774330
14/866681
all
Broadly directed to any dsRNA with specific modifications and/or characteristics
9938530
15/041738
all
Claims broadly recite compounds that inhibit a gene encoding TGFB1 or TGFB2.
9963702
15/099481
all
Claims broadly recite compounds that inhibit a gene encoding CTGF.
RE46873 E
15/166223
all
Claims broadly recite compounds that inhibit a gene encoding TGFB1 or TGFB2.
10913948
15/918605
all
Claims broadly recite treating a fibrotic disorder.
11396654
16/159590
all
Claims are broadly directed to any dsRNA with specific modifications and/or characteristics
11015198
16/497000
all
Broadly directed to any dsRNA with specific modifications and/or characteristics
11414660
16/500770
all
Broadly directed to any dsRNA with specific modifications and/or characteristics
11299738
16/603211
all
Claim 15 recites treating a cardiovascular disease
12084656
17/219265
all
Broadly directed to any dsRNA with specific modifications and/or characteristics s
11987794
17/688789
All
Broadly directed to any dsRNA with specific modifications and/or characteristics
12378552
17/720129
all
Claim 7 describes treating cardiovascular disease (i.e., stroke, thrombosis, and myocardial infarction)
12600967
17/867404
all
Claim 9 describes treating cardiovascular disease (i.e., myocardial infarction)
Although the claims at issue are not identical, they are directed to overlapping subject matter because both claim sets are directed to dsRNAs that could be used in the same nucleic acid construct that would have been obvious in view of the prior art.
The instant claims are directed to nucleic acid constructs for targeting PCSK9 and APOC3 and additional target mRNAs (additional nucleic acid portions). The instant claims recite specific SEQ ID NOs that target PCSK9 and APOC3, that the nucleic acid construct can comprise modifications, linkers, modification patterns, pharmaceutical compositions, and additional agents including additional target mRNAs.
The patented claims are all directed to dsRNAs/oligomeric or nucleic acid compounds that could be used as the additional nucleic acid portions/additional agents, or to methods of using the dsRNAs/oligomeric or nucleic acid compounds. The patented claims are broadly drawn to either: (1) any dsRNA with specific modifications and/or characteristics, (2) claims that recite treating a fibrotic disorder, or (3) claims that broadly recite inhibiting TGFβ1.
The patented claims do not teach every aspect of the claimed invention. However, all those elements are made obvious by the prior art:
WO602 teaches (§Abstract, p. 5 L24-30) multi-targeting nucleic acid construct that comprise 2 or more dsRNAs connected via a labile functionality such that, in vivo , the construct disassembles to yield discrete nucleic acid targeting molecules that target respective mRNA and which construct can comprise additional dsRNA for targeting 1-8 additional gene(s).WO602 teaches (p. 4 L23-30; pp. 6-7 L1-31; p. 8 L24-37; p. 9-13 L4-25; pp. 9-10 L25-4; pp. 10-12 L5-16; pp. 12-13 L18-16; p. 13 L15-25; p. 15 L15-25; pp. 17-19 L30-35; p. 18 L10-26; p. 19 L10-20; pp. 46-47; Figs. 2-3, 5; Table 3, starts on p. 25;) the structures, modifications, modification patterns, design scheme, pharmaceutical composition, and additional lipid-lowering agent(s) of the instant claims.
Ruotsalainen teaches (§Introduction ¶1, §PCSK9 ¶1, Table 1, §ApoCIII ¶1-3, Table 1, §Advantages and Challenges of RNAi-Based Therapeutics in Lipid Lowering) RNAi-based therapies and combination therapies for atherosclerosis and other cardiovascular diseases (CVD). Ruotsalainen teaches dsRNA therapies that target PCSK9 and APOC3.
Regarding the PCSK9-targeting oligont, WO472 teaches (pp. 4-5 L20-14; p. 82 item 20; pp. 12-14 L25-28; p. 24 L30-35; p. 6 L14-16, p. 27, full ¶2) sequences (including SEQ ID NO 1355), modifications, dsRNAs and elements of dsRNA design that make obvious the claimed SEQ ID NOs. WO472 teaches (p. 3 L8-15) their dsRNA are for treating CVD and dislipidemia.
Regarding the APOC3-targeting oligont, WO615 teaches (¶12-13, ¶16, ¶364, Table 7, ¶40, ¶163, ¶191) sequences (including SEQ ID NOs 53-54), modifications, dsRNAs and elements of dsRNA design that make obvious the claimed SEQ ID NOs. WO615 teaches (§Abstract) their dsRNA are for treating lipid diseases including hypercholesterolemia and dyslipidemia.
Regarding the AS strands wherein the 5’ nt is a U mismatch to the target mRNA, Kamola, drawn to principles of rational sequence design for siRNAs, teaches (§Discussion ¶2) benefits of producing siRNAs that comprise A/U at the 5’end of the guide strands.
An artisan would have understood that the dsRNA of the patented claims could be used in any invention requiring a nucleic acid construct and/or treating a fibrotic disorder (including by inhibiting CTGF) or inhibiting TGFβ1 would be beneficial for treating CVD because Vanio teaches (§Highlights and §Abstract) inhibiting CTGF using an antibody is beneficial for treating cardiac fibrosis and other heart conditions, and because Goumans teaches (§TGF-β SIGNALING IN CARDIAC FIBROSIS ¶2) inhibiting TGFβ signaling decreases cardiac fibrosis and improves cardiac function.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA of the patented claims with the nucleic acid construct of WO602, the combination therapy of Ruotsalainen, the AS strand sequences of WO472 and WO615, and the teachings of Kamola for the benefit of producing a combination PCSK9- and APOC3-targeting construct according to the various nucleic acid construct designs of WO602 and using it to treat CVD. One would have been motivated to do so with a reasonable expectation of success because WO602 teaches (p. 4 25-30) their design schemes improve upon shortcomings of complementary oligonucleotide technologies, such as high product cost, suboptimal efficacy/specificity, low stability, and difficulty of delivery. One would have done so for the benefit of treating CVD by modulating at least two different pathways. One would have been motivated to do so with a reasonable expectation of success because WO602 teaches that their multi-targeting construct can target any two or more genes and Ruotsalainen teaches using combination therapies to treat CVD provides great improvements to patients. It would have been a simple matter to use the AS strands from WO472 and WO615, optimize them as taught by Kamola, design appropriate sense strands, and then incorporate them into the designs of WO602. It would have been obvious to incorporate the dsRNA of the patented claims because WO602 teaches (cited above) incorporating additional dsRNA and teachings of Vanio and Goumans indicate that the dsRNA of the patented claims would be beneficial for treating CVD or CVD-related conditions.
Therefore the instant claims would have been obvious in view of the dsRNA of the patented claims and the prior art of WO602, Ruotsalainen, WO472, WO615, Kamola, Vanio, and Goumans.
Claims 1-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the following claims of the following copending Applications in view of in view of WO602, Ruotsalainen, WO472, WO615, and Kamola.
Copending App. #
Claims
Additional notes
17/042946
all
Claims are broadly directed to any dsRNA with specific modifications and/or characteristics
17/215964
all
Claims are broadly directed to any dsRNA with specific modifications and/or characteristics
18/365052
all
Claim 19 recites treating CVD (i.e., hypertension)
18/797143
all
Claims are broadly directed to any nucleic acid for inhibiting a target gene and which comprises specific modifications and/or characteristics
18/974081
all
Claim 175 recites using the oligomeric compound to treat CVD (i.e., coronary artery disease)
18/982618
all
Claim 175 recites using the oligomeric compound to treat CVD (i.e., myocardial infarction, coronary artery disease)
19/290319
all
Claim 175 recites using the nucleic acid construct to reduce cholesterol and lipid levels
19/290323
all
Claim 176 recites using the nucleic acid construct to reduce cholesterol and lipid levels and treat CVD
Although the claims at issue are not identical, they are directed to overlapping subject matter because both claim sets are directed to dsRNAs that could be used in the same nucleic acid construct that would have been obvious in view of the prior art.
The instant claims are directed to nucleic acid constructs for targeting PCSK9 and APOC3 and additional target mRNAs (additional nucleic acid portions). The instant claims recite specific SEQ ID NOs that target PCSK9 and APOC3, that the nucleic acid construct can comprise modifications, linkers, modification patterns, pharmaceutical compositions, and additional agents including additional target mRNAs.
The copending claims are all directed to dsRNAs/oligomeric or nucleic acid compounds that could be used as the additional nucleic acid portions/additional agents, or to methods of using the dsRNAs/oligomeric or nucleic acid compounds. The copending claims are broadly drawn to either: (1) any dsRNA with specific modifications and/or characteristics or (2) claims that recite treating CVD or CVD-related conditions.
The copending claims do not teach every aspect of the claimed invention. However, all those elements are made obvious by the prior art:
WO602 teaches (§Abstract, p. 5 L24-30) multi-targeting nucleic acid construct that comprise 2 or more dsRNAs connected via a labile functionality such that, in vivo , the construct disassembles to yield discrete nucleic acid targeting molecules that target respective mRNA and which construct can comprise additional dsRNA for targeting 1-8 additional gene(s).WO602 teaches (p. 4 L23-30; pp. 6-7 L1-31; p. 8 L24-37; p. 9-13 L4-25; pp. 9-10 L25-4; pp. 10-12 L5-16; pp. 12-13 L18-16; p. 13 L15-25; p. 15 L15-25; pp. 17-19 L30-35; p. 18 L10-26; p. 19 L10-20; pp. 46-47; Figs. 2-3, 5; Table 3, starts on p. 25;) the structures, modifications, modification patterns, design scheme, pharmaceutical composition, and additional lipid-lowering agent(s) of the instant claims.
Ruotsalainen teaches (§Introduction ¶1, §PCSK9 ¶1, Table 1, §ApoCIII ¶1-3, Table 1, §Advantages and Challenges of RNAi-Based Therapeutics in Lipid Lowering) RNAi-based therapies and combination therapies for atherosclerosis and other cardiovascular diseases (CVD). Ruotsalainen teaches dsRNA therapies that target PCSK9 and APOC3.
Regarding the PCSK9-targeting oligont, WO472 teaches (pp. 4-5 L20-14; p. 82 item 20; pp. 12-14 L25-28; p. 24 L30-35; p. 6 L14-16, p. 27, full ¶2) sequences (including SEQ ID NO 1355), modifications, dsRNAs and elements of dsRNA design that make obvious the claimed SEQ ID NOs. WO472 teaches (p. 3 L8-15) their dsRNA are for treating CVD and dislipidemia.
Regarding the APOC3-targeting oligont, WO615 teaches (¶12-13, ¶16, ¶364, Table 7, ¶40, ¶163, ¶191) sequences (including SEQ ID NOs 53-54), modifications, dsRNAs and elements of dsRNA design that make obvious the claimed SEQ ID NOs. WO615 teaches (§Abstract) their dsRNA are for treating lipid diseases including hypercholesterolemia and dyslipidemia.
Regarding the AS strands wherein the 5’ nt is a U mismatch to the target mRNA, Kamola, drawn to principles of rational sequence design for siRNAs, teaches (§Discussion ¶2) benefits of producing siRNAs that comprise A/U at the 5’end of the guide strands.
An artisan would have understood that the dsRNA of the copending claims could be used in any invention requiring a nucleic acid construct and/or treating CVD because Ruotsalainen teaches combination therapies for treating CVD and WO602 teaches incorporating up to a total of 10 dsRNA in their design.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA of the copending claims with the nucleic acid construct of WO602, the combination therapy of Ruotsalainen, the AS strand sequences of WO472 and WO615, and the teachings of Kamola for the benefit of producing a combination PCSK9- and APOC3-targeting construct according to the various nucleic acid construct designs of WO602 and using it to treat CVD. One would have been motivated to do so with a reasonable expectation of success because WO602 teaches (p. 4 25-30) their design schemes improve upon shortcomings of complementary oligonucleotide technologies, such as high product cost, suboptimal efficacy/specificity, low stability, and difficulty of delivery. One would have done so for the benefit of treating CVD by modulating at least two different pathways. One would have been motivated to do so with a reasonable expectation of success because WO602 teaches that their multi-targeting construct can target any two or more genes and Ruotsalainen teaches using combination therapies to treat CVD provides great improvements to patients. It would have been a simple matter to use the AS strands from WO472 and WO615, optimize them as taught by Kamola, design appropriate sense strands, and then incorporate them into the designs of WO602. It would have been obvious to incorporate the dsRNA of the copending claims because WO602 teaches (cited above) incorporating additional dsRNA and the copending claims recite using their compounds or methods for treating CVD or CVD-related conditions.
Therefore the instant claims would have been obvious in view of the dsRNA of the copending claims and the prior art of WO602, Ruotsalainen, WO472, WO615, and Kamola.
This is a provisional nonstatutory double patenting rejection.
Claims 1-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-8 of US Patent No. 12612626 (issued 28 April 2026, “US626”) in view of in view of WO602, WO472, and Kamola.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to nucleic acid constructs for targeting PCSK9 and APOC3 and additional target mRNAs (additional nucleic acid portions). The instant claims recite specific SEQ ID NOs that target PCSK9 and APOC3, that the nucleic acid construct can comprise modifications, linkers, modification patterns, pharmaceutical compositions, and additional agents including additional target mRNAs.
The patented US626 claims are all directed to dsRNAs for inhibiting expression of APOC3 and which comprise certain SEQ ID NOs, and wherein the dsRNAs can comprise certain modifications, to a pharmaceutical composition comprising the dsRNA that can comprise further agents and a dsRNA that targets PCSK9, and to methods or using the dsRNA to treat disorders. The US626 claims recite APOC3-targeting sequences SEQ ID NOs 28 and 428 which are identical to claimed SEQ ID NOs 10 and 24 as shown by the following alignments:
US-17-849-382-28
Filing date in PALM: 2022-06-24
Sequence 28, US/17849382
Publication No. US20230089915A1
GENERAL INFORMATION
APPLICANT: SIRNAOMICS, INC.
TITLE OF INVENTION: PRODUCTS AND COMPOSITIONS
FILE REFERENCE: 4690.0050C
CURRENT APPLICATION NUMBER: US/17/849,382
CURRENT FILING DATE: 2022-06-24
PRIOR APPLICATION NUMBER: 63/318,287
PRIOR FILING DATE: 2022-03-09
PRIOR APPLICATION NUMBER: 63/214,608
PRIOR FILING DATE: 2021-06-24
NUMBER OF SEQ ID NOS: 1606
SEQ ID NO 28
LENGTH: 19
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
Oligonucleotide
ALIGNMENT:
Query Match 100.0%; Score 19; Length 19;
Best Local Similarity 89.5%;
Matches 17; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TCAACAAGGAGTACCCGGG 19
:||||||||||:|||||||
Db 1 UCAACAAGGAGUACCCGGG 19
US-17-849-382-428
Filing date in PALM: 2022-06-24
Sequence 428, US/17849382
Publication No. US20230089915A1
GENERAL INFORMATION
APPLICANT: SIRNAOMICS, INC.
TITLE OF INVENTION: PRODUCTS AND COMPOSITIONS
FILE REFERENCE: 4690.0050C
CURRENT APPLICATION NUMBER: US/17/849,382
CURRENT FILING DATE: 2022-06-24
PRIOR APPLICATION NUMBER: 63/318,287
PRIOR FILING DATE: 2022-03-09
PRIOR APPLICATION NUMBER: 63/214,608
PRIOR FILING DATE: 2021-06-24
NUMBER OF SEQ ID NOS: 1606
SEQ ID NO 428
LENGTH: 15
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
Oligonucleotide
ALIGNMENT:
Query Match 100.0%; Score 15; Length 15;
Best Local Similarity 60.0%;
Matches 9; Conservative 6; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGTACTCCTTGTTGA 15
||:||:||::|::||
Db 1 GGUACUCCUUGUUGA 15
The patented US626 claims do not teach every aspect of the claimed invention. However, all those elements are made obvious by the prior art:
WO602 teaches (§Abstract, p. 5 L24-30) multi-targeting nucleic acid construct that comprise 2 or more dsRNAs connected via a labile functionality such that, in vivo , the construct disassembles to yield discrete nucleic acid targeting molecules that target respective mRNA and which construct can comprise additional dsRNA for targeting 1-8 additional gene(s).WO602 teaches (p. 4 L23-30; pp. 6-7 L1-31; p. 8 L24-37; p. 9-13 L4-25; pp. 9-10 L25-4; pp. 10-12 L5-16; pp. 12-13 L18-16; p. 13 L15-25; p. 15 L15-25; pp. 17-19 L30-35; p. 18 L10-26; p. 19 L10-20; pp. 46-47; Figs. 2-3, 5; Table 3, starts on p. 25;) the structures, modifications, modification patterns, design scheme, pharmaceutical composition, and additional lipid-lowering agent(s) of the instant claims.
Regarding the PCSK9-targeting oligont, WO472 teaches (pp. 4-5 L20-14; p. 82 item 20; pp. 12-14 L25-28; p. 24 L30-35; p. 6 L14-16, p. 27, full ¶2) sequences (including SEQ ID NO 1355), modifications, dsRNAs and elements of dsRNA design that make obvious the claimed SEQ ID NOs. WO472 teaches (p. 3 L8-15) their dsRNA are for treating CVD and dislipidemia.
Regarding the AS strands wherein the 5’ nt is a U mismatch to the target mRNA, Kamola, drawn to principles of rational sequence design for siRNAs, teaches (§Discussion ¶2) benefits of producing siRNAs that comprise A/U at the 5’end of the guide strands.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA of the patented claims with the nucleic acid construct of WO602, the AS strand sequences of WO472, and the teachings of Kamola for the benefit of producing a combination PCSK9- and APOC3-targeting construct according to the various nucleic acid construct designs of WO602 and using it to treat CVD. One would have been motivated to do so with a reasonable expectation of success because the US626 claims recite a combination therapy comprising a PCKS9-targeting agent and because WO602 teaches (p. 4 25-30) their design schemes improve upon shortcomings of complementary oligonucleotide technologies, such as high product cost, suboptimal efficacy/specificity, low stability, and difficulty of delivery. One would have done so for the benefit of administering a PCKS9-inhibiting treatment and one would have been motivated to do so with a reasonable expectation of success because the US626 claims recite doing so and because WO602 teaches that their multi-targeting construct can target any two or more genes. It would have been a simple matter to use the AS strands from WO472, optimize them as taught by Kamola, design appropriate sense strands, and then incorporate them into the designs of WO602. It would have been obvious to incorporate the dsRNA of the patented claims because the US626 claims and WO602 teach (cited above) incorporating additional dsRNA.
Therefore the instant claims would have been obvious in view of the dsRNA of the patented claims and the prior art of WO602, WO472, and Kamola.
This is a provisional nonstatutory double patenting rejection.
Claims 1-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the all pending claims of the copending Application No. 18/977340 (“App340”) in view of in view of WO602, WO472, and Kamola.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to nucleic acid constructs for targeting PCSK9 and APOC3 and additional target mRNAs (additional nucleic acid portions). The instant claims recite specific SEQ ID NOs that target PCSK9 and APOC3, that the nucleic acid construct can comprise modifications, linkers, modification patterns, pharmaceutical compositions, and additional agents including additional target mRNAs.
The copending App340 claims are all directed to nucleic acid constructs comprising dsRNAs for inhibiting expression of APOC3 (which dsRNA comprise certain SEQ ID NOs) and another dsRNA, and wherein the nucleic acid construct can comprise certain modifications, to a pharmaceutical composition comprising the nucleic acid construct, and to methods or using the nucleic acid construct to treat disorders. The copending App340 claims recite APOC3-targeting sequences SEQ ID NOs 10 and 24 which are identical to claimed SEQ ID NOs 10 and 24 as shown by the following alignments:
US-18-977-340-10
Filing date in PALM: 2024-12-11
Sequence 10, US/18977340
Publication No. US20250313846A1
GENERAL INFORMATION
APPLICANT: SIRNAOMICS, INC. (en)
TITLE OF INVENTION: PRODUCTS AND COMPOSITIONS (en)
FILE REFERENCE: 4690.0071I
CURRENT APPLICATION NUMBER: US/18/977,340
CURRENT FILING DATE: 2024-12-11
NUMBER OF SEQ ID NOS: 672
SEQ ID NO 10
LENGTH: 19
TYPE: DNA
FEATURE:
NAME/KEY: source
LOCATION: 1..19
QUALIFIERS: mol_type = other RNA
organism = synthetic construct
ALIGNMENT:
Query Match 100.0%; Score 19; Length 19;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TCAACAAGGAGTACCCGGG 19
|||||||||||||||||||
Db 1 TCAACAAGGAGTACCCGGG 19
US-18-977-340-24
Filing date in PALM: 2024-12-11
Sequence 24, US/18977340
Publication No. US20250313846A1
GENERAL INFORMATION
APPLICANT: SIRNAOMICS, INC. (en)
TITLE OF INVENTION: PRODUCTS AND COMPOSITIONS (en)
FILE REFERENCE: 4690.0071I
CURRENT APPLICATION NUMBER: US/18/977,340
CURRENT FILING DATE: 2024-12-11
NUMBER OF SEQ ID NOS: 672
SEQ ID NO 24
LENGTH: 15
TYPE: DNA
FEATURE:
NAME/KEY: source
LOCATION: 1..15
QUALIFIERS: mol_type = other RNA
organism = synthetic construct
ALIGNMENT:
Query Match 100.0%; Score 15; Length 15;
Best Local Similarity 100.0%;
Matches 15; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGTACTCCTTGTTGA 15
|||||||||||||||
Db 1 GGTACTCCTTGTTGA 15
The copending App340 claims do not teach every aspect of the claimed invention. However, all those elements are made obvious by the prior art:
WO602 teaches (§Abstract, p. 5 L24-30) multi-targeting nucleic acid construct that comprise 2 or more dsRNAs connected via a labile functionality such that, in vivo , the construct disassembles to yield discrete nucleic acid targeting molecules that target respective mRNA and which construct can comprise additional dsRNA for targeting 1-8 additional gene(s).WO602 teaches (p. 4 L23-30; pp. 6-7 L1-31; p. 8 L24-37; p. 9-13 L4-25; pp. 9-10 L25-4; pp. 10-12 L5-16; pp. 12-13 L18-16; p. 13 L15-25; p. 15 L15-25; pp. 17-19 L30-35; p. 18 L10-26; p. 19 L10-20; pp. 46-47; Figs. 2-3, 5; Table 3, starts on p. 25;) the structures, modifications, modification patterns, design scheme, pharmaceutical composition, and additional lipid-lowering agent(s) of the instant claims.
Regarding the PCSK9-targeting oligont, WO472 teaches (pp. 4-5 L20-14; p. 82 item 20; pp. 12-14 L25-28; p. 24 L30-35; p. 6 L14-16, p. 27, full ¶2) sequences (including SEQ ID NO 1355), modifications, dsRNAs and elements of dsRNA design that make obvious the claimed SEQ ID NOs. WO472 teaches (p. 3 L8-15) their dsRNA are for treating CVD and dislipidemia.
Regarding the AS strands wherein the 5’ nt is a U mismatch to the target mRNA, Kamola, drawn to principles of rational sequence design for siRNAs, teaches (§Discussion ¶2) benefits of producing siRNAs that comprise A/U at the 5’end of the guide strands.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA of the copending App340 claims with the nucleic acid construct of WO602, the AS strand sequences of WO472, and the teachings of Kamola for the benefit of producing a combination PCSK9- and APOC3-targeting construct according to the various nucleic acid construct designs of WO602 and using it to treat CVD. One would have been motivated to do so with a reasonable expectation of success WO602 teaches (p. 4 25-30) their design schemes improve upon shortcomings of complementary oligonucleotide technologies, such as high product cost, suboptimal efficacy/specificity, low stability, and difficulty of delivery. One would have done so for the benefit of administering a PCKS9-inhibiting treatment and one would have been motivated to do so with a reasonable expectation of success because WO602 teaches that their multi-targeting construct can target any two or more genes. It would have been a simple matter to use the AS strands from WO472, optimize them as taught by Kamola, design appropriate sense strands, and then incorporate them into the designs of WO602. It would have been obvious to incorporate the dsRNA of the copending claims because the WO602 teach (cited above) incorporating additional dsRNA.
Therefore the instant claims would have been obvious in view of the dsRNA of the copending App340 claims and the prior art of WO602, WO472, and Kamola.
This is a provisional nonstatutory double patenting rejection.
Claims 1-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the all pending claims of the copending Application No. 19/142520 (“App520”) in view of in view of WO472 and Kamola.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to nucleic acid constructs for targeting PCSK9 and APOC3 and additional target mRNAs (additional nucleic acid portions). The instant claims recite specific SEQ ID NOs that target PCSK9 and APOC3, that the nucleic acid construct can comprise modifications, linkers, modification patterns, pharmaceutical compositions, and additional agents including additional target mRNAs.
The copending App520 claims are all directed to nucleic acid constructs comprising dsRNAs for inhibiting expression of APOC3 (which dsRNA comprise certain SEQ ID NOs) and another dsRNA, and wherein the nucleic acid construct can comprise additional dsRNAs, can comprise certain modifications, to a pharmaceutical composition comprising the nucleic acid construct, and to methods or using the nucleic acid construct to treat CVD. The copending App520 claims recite APOC3-targeting sequences SEQ ID NOs 3 and 33 which are identical to claimed SEQ ID NOs 10 and 24 as shown by the following alignments:
US-19-142-520-3
Filing date in PALM: N/A
Sequence 3, US/19142520
GENERAL INFORMATION
APPLICANT: SIRNAOMICS, INC. (en)
TITLE OF INVENTION: PRODUCTS AND COMPOSITIONS (en)
FILE REFERENCE: 4690.0082I
CURRENT APPLICATION NUMBER: US/19/142,520
CURRENT FILING DATE: 2025-06-23
NUMBER OF SEQ ID NOS: 166
SEQ ID NO 3
LENGTH: 19
TYPE: DNA
FEATURE:
NAME/KEY: source
LOCATION: 1..19
QUALIFIERS: mol_type = other DNA
organism = synthetic construct
ALIGNMENT:
Query Match 100.0%; Score 19; Length 19;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TCAACAAGGAGTACCCGGG 19
|||||||||||||||||||
Db 1 TCAACAAGGAGTACCCGGG 19
US-19-142-520-33
Filing date in PALM: N/A
Sequence 33, US/19142520
GENERAL INFORMATION
APPLICANT: SIRNAOMICS, INC. (en)
TITLE OF INVENTION: PRODUCTS AND COMPOSITIONS (en)
FILE REFERENCE: 4690.0082I
CURRENT APPLICATION NUMBER: US/19/142,520
CURRENT FILING DATE: 2025-06-23
NUMBER OF SEQ ID NOS: 166
SEQ ID NO 33
LENGTH: 15
TYPE: DNA
FEATURE:
NAME/KEY: source
LOCATION: 1..15
QUALIFIERS: mol_type = other DNA
organism = synthetic construct
ALIGNMENT:
Query Match 100.0%; Score 15; Length 15;
Best Local Similarity 100.0%;
Matches 15; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGTACTCCTTGTTGA 15
|||||||||||||||
Db 1 GGTACTCCTTGTTGA 15
The copending App520 claims do not teach every aspect of the claimed invention. However, all those elements are made obvious by the prior art:
Regarding the PCSK9-targeting oligont, WO472 teaches (pp. 4-5 L20-14; p. 82 item 20; pp. 12-14 L25-28; p. 24 L30-35; p. 6 L14-16, p. 27, full ¶2) sequences (including SEQ ID NO 1355), modifications, dsRNAs and elements of dsRNA design that make obvious the claimed SEQ ID NOs. WO472 teaches (p. 3 L8-15) their dsRNA are for treating CVD and dislipidemia.
Regarding the AS strands wherein the 5’ nt is a U mismatch to the target mRNA, Kamola, drawn to principles of rational sequence design for siRNAs, teaches (§Discussion ¶2) benefits of producing siRNAs that comprise A/U at the 5’end of the guide strands.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA of the copending claims with the AS strand sequences of WO472 and the teachings of Kamola for the benefit of producing a combination PCSK9- and APOC3-targeting construct according to the various nucleic acid construct designs of the copending App520 claims, and using it to treat CVD. One would have been motivated to do so with a reasonable expectation of success because the copending App520 claims recite a combination therapy comprising a lipid-lowering agents and because WO472 teaches PCSK9-targeting dsRNA and makes obvious the instantly claimed SEQ ID NOs. One would have done so for the benefit of administering a PCKS9-inhibiting treatment and one would have been motivated to do so with a reasonable expectation of success because the copending App520 claims recite additional dsRNA and that their multi-targeting construct can target any two or more genes. It would have been a simple matter to use the AS strands from WO472, optimize them as taught by Kamola, design appropriate sense strands, and then incorporate them into the designs of the copending App520 claims.
Therefore the instant claims would have been obvious in view of the dsRNA of the copending App520 claims and the prior art of WO472 and Kamola.
This is a provisional nonstatutory double patenting rejection.
Claims 1-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the all pending claims of the copending Application No. 19082160 (“App160”) in view of in view of WO602.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to nucleic acid constructs for targeting PCSK9 and APOC3 and additional target mRNAs (additional nucleic acid portions). The instant claims recite specific SEQ ID NOs that target PCSK9 and APOC3, that the nucleic acid construct can comprise modifications, linkers, modification patterns, pharmaceutical compositions, and additional agents including additional target mRNAs.
The copending App160 claims are all directed to nucleic acid constructs comprising dsRNAs for inhibiting expression of AGT and at least another target gene but which constructs can comprise additional dsRNAs for additional target genes, wherein the target genes can be APOC3 and PCKS9; wherein the nucleic acid constructs can comprise certain modifications, to a pharmaceutical composition comprising the nucleic acid construct, and to methods or using the nucleic acid construct to treat CVD. The copending App160 claims recite APOC3-targeting sequences SEQ ID NOs 1004 and 1756 which are identical to claimed SEQ ID NOs 10 and 24 as shown by the following alignments:
US-19-082-160-1004
Filing date in PALM: 2025-03-17
Sequence 1004, US/19082160
GENERAL INFORMATION
APPLICANT: SIRNAOMICS, INC. (en)
TITLE OF INVENTION: PRODUCTS AND COMPOSITIONS (en)
FILE REFERENCE: 4690.0081I
CURRENT APPLICATION NUMBER: US/19/082,160
CURRENT FILING DATE: 2025-03-17
NUMBER OF SEQ ID NOS: 3605
SEQ ID NO 1004
LENGTH: 19
TYPE: DNA
FEATURE:
NAME/KEY: source
LOCATION: 1..19
QUALIFIERS: mol_type = other RNA
organism = synthetic construct
FEATURE:
NAME/KEY: modified_base
LOCATION: 1
QUALIFIERS: mod_base = OTHER
note = 5'-phosphate-2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 2
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 3
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 4
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 5
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 6
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 7
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 8
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 9
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 10
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 11
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 12
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 13
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 14
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 15
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 16
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 17
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 18
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 19
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
ALIGNMENT:
Query Match 100.0%; Score 19; Length 19;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TCAACAAGGAGTACCCGGG 19
|||||||||||||||||||
Db 1 TCAACAAGGAGTACCCGGG 19
US-19-082-160-1756
Filing date in PALM: 2025-03-17
Sequence 1756, US/19082160
GENERAL INFORMATION
APPLICANT: SIRNAOMICS, INC. (en)
TITLE OF INVENTION: PRODUCTS AND COMPOSITIONS (en)
FILE REFERENCE: 4690.0081I
CURRENT APPLICATION NUMBER: US/19/082,160
CURRENT FILING DATE: 2025-03-17
NUMBER OF SEQ ID NOS: 3605
SEQ ID NO 1756
LENGTH: 15
TYPE: DNA
FEATURE:
NAME/KEY: source
LOCATION: 1..15
QUALIFIERS: mol_type = other RNA
organism = synthetic construct
FEATURE:
NAME/KEY: modified_base
LOCATION: 1
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 2
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 3
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 4
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 5
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 6
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 7
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 8
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 9
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 10
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 11
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 12
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 13
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 14
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 15
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
ALIGNMENT:
Query Match 100.0%; Score 15; Length 15;
Best Local Similarity 100.0%;
Matches 15; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGTACTCCTTGTTGA 15
|||||||||||||||
Db 1 GGTACTCCTTGTTGA 15
The copending App160 claims recite PCKS9-targeting sequences SEQ ID NOs 2192 and 3021 which are identical to claimed SEQ ID NOs 4 and 18 as shown by the following alignments:
US-19-082-160-2192
Filing date in PALM: 2025-03-17
Sequence 2192, US/19082160
GENERAL INFORMATION
APPLICANT: SIRNAOMICS, INC. (en)
TITLE OF INVENTION: PRODUCTS AND COMPOSITIONS (en)
FILE REFERENCE: 4690.0081I
CURRENT APPLICATION NUMBER: US/19/082,160
CURRENT FILING DATE: 2025-03-17
NUMBER OF SEQ ID NOS: 3605
SEQ ID NO 2192
LENGTH: 19
TYPE: DNA
FEATURE:
NAME/KEY: source
LOCATION: 1..19
QUALIFIERS: mol_type = other RNA
organism = synthetic construct
FEATURE:
NAME/KEY: modified_base
LOCATION: 1
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide with
phosphorothioate linkage
FEATURE:
NAME/KEY: modified_base
LOCATION: 2
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide with
phosphorothioate linkage
FEATURE:
NAME/KEY: modified_base
LOCATION: 3
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 4
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 5
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 6
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 7
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 8
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 9
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 10
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 11
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 12
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 13
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 14
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide with phosphorothioate
linkage
FEATURE:
NAME/KEY: modified_base
LOCATION: 15
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide with
phosphorothioate linkage
FEATURE:
NAME/KEY: modified_base
LOCATION: 16
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide with
phosphorothioate linkage
FEATURE:
NAME/KEY: modified_base
LOCATION: 17
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide with
phosphorothioate linkage
FEATURE:
NAME/KEY: modified_base
LOCATION: 18
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide with
phosphorothioate linkage
ALIGNMENT:
Query Match 100.0%; Score 19; Length 19;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TGCAAAACAGGTCTAGAAA 19
|||||||||||||||||||
Db 1 TGCAAAACAGGTCTAGAAA 19
US-19-082-160-3021
Filing date in PALM: 2025-03-17
Sequence 3021, US/19082160
GENERAL INFORMATION
APPLICANT: SIRNAOMICS, INC. (en)
TITLE OF INVENTION: PRODUCTS AND COMPOSITIONS (en)
FILE REFERENCE: 4690.0081I
CURRENT APPLICATION NUMBER: US/19/082,160
CURRENT FILING DATE: 2025-03-17
NUMBER OF SEQ ID NOS: 3605
SEQ ID NO 3021
LENGTH: 15
TYPE: DNA
FEATURE:
NAME/KEY: source
LOCATION: 1..15
QUALIFIERS: mol_type = other RNA
organism = synthetic construct
FEATURE:
NAME/KEY: modified_base
LOCATION: 1
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 2
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 3
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 4
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 5
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 6
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 7
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 8
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 9
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 10
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 11
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 12
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 13
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 14
QUALIFIERS: mod_base = OTHER
note = 2'-O-methyl modified nucleotide
FEATURE:
NAME/KEY: modified_base
LOCATION: 15
QUALIFIERS: mod_base = OTHER
note = 2'-fluoro modified nucleotide
ALIGNMENT:
Query Match 100.0%; Score 15; Length 15;
Best Local Similarity 100.0%;
Matches 15; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TAGACCTGTTTTGCA 15
|||||||||||||||
Db 1 TAGACCTGTTTTGCA 15
The copending App160 claims do not teach every aspect of the claimed invention. However, all those elements are made obvious by the prior art:
WO602 teaches (§Abstract, p. 5 L24-30) multi-targeting nucleic acid construct that comprise 2 or more dsRNAs connected via a labile functionality such that, in vivo , the construct disassembles to yield discrete nucleic acid targeting molecules that target respective mRNA and which construct can comprise additional dsRNA for targeting 1-8 additional gene(s).WO602 teaches (p. 4 L23-30; pp. 6-7 L1-31; p. 8 L24-37; p. 9-13 L4-25; pp. 9-10 L25-4; pp. 10-12 L5-16; pp. 12-13 L18-16; p. 13 L15-25; p. 15 L15-25; pp. 17-19 L30-35; p. 18 L10-26; p. 19 L10-20; pp. 46-47; Figs. 2-3, 5; Table 3, starts on p. 25;) the structures, modifications, modification patterns, design scheme, pharmaceutical composition, and additional lipid-lowering agent(s) of the instant claims.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA of the patented/copending App160 claims with the teachings of WO602. One would have been motivated to do so with a reasonable expectation of success because the copending App160 claims recite a combination therapy and recite PCSK9- and APOC3-targeting dsRNA. One would have done so for the benefit of administering a PCKS9-inhibiting treatment and one would have been motivated to do so with a reasonable expectation of success because the copending App160 claims recite additional dsRNA and that their multi-targeting construct can target any two or more genes. Any combinations of the App160 claimed SEQ ID NOs would have been obvious in view of the design schemes of WO602.
Therefore the instant claims would have been obvious in view of the dsRNA of the copending App160 claims and the prior art of WO602.
This is a provisional nonstatutory double patenting rejection.
Claims 1-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the all pending claims of the copending Application No. 19412066 (“App066”) in view of in view of WO602, WO615, and Kamola.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to nucleic acid constructs for targeting PCSK9 and APOC3 and additional target mRNAs (additional nucleic acid portions). The instant claims recite specific SEQ ID NOs that target PCSK9 and APOC3, that the nucleic acid construct can comprise modifications, linkers, modification patterns, pharmaceutical compositions, and additional agents including additional target mRNAs.
The copending App066 claims are all directed to nucleic acid constructs comprising dsRNAs for inhibiting expression of PCSK9 (which dsRNA comprise certain SEQ ID NOs) and can comprise (Claim 82) another dsRNA, and wherein the nucleic acid construct can comprise certain modifications, to a pharmaceutical composition comprising the nucleic acid construct, and to methods or using the nucleic acid construct to treat disorders. The copending App066 claims recite PCSK9-targeting sequences SEQ ID NOs 29 and 279 which are identical to claimed SEQ ID NOs 4 and 18 as shown by the following alignments (Note that alignments are shown to App066 parent Application No. 17/843657 because App066 has no SEQ listing):
US-17-843-657-29
Query Match 100.0%; Score 19; DB 1; Length 19;
Best Local Similarity 84.2%;
Matches 16; Conservative 3; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TGCAAAACAGGTCTAGAAA 19
:||||||||||:|:|||||
Db 1 UGCAAAACAGGUCUAGAAA 19
US-17-843-657-279
Query Match 100.0%; Score 15; DB 1; Length 15;
Best Local Similarity 60.0%;
Matches 9; Conservative 6; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TAGACCTGTTTTGCA 15
:|||||:|::::|||
Db 1 UAGACCUGUUUUGCA 15
The copending App066 claims do not teach every aspect of the claimed invention. However, all those elements are made obvious by the prior art:
WO602 teaches (§Abstract, p. 5 L24-30) multi-targeting nucleic acid construct that comprise 2 or more dsRNAs connected via a labile functionality such that, in vivo , the construct disassembles to yield discrete nucleic acid targeting molecules that target respective mRNA and which construct can comprise additional dsRNA for targeting 1-8 additional gene(s).WO602 teaches (p. 4 L23-30; pp. 6-7 L1-31; p. 8 L24-37; p. 9-13 L4-25; pp. 9-10 L25-4; pp. 10-12 L5-16; pp. 12-13 L18-16; p. 13 L15-25; p. 15 L15-25; pp. 17-19 L30-35; p. 18 L10-26; p. 19 L10-20; pp. 46-47; Figs. 2-3, 5; Table 3, starts on p. 25;) the structures, modifications, modification patterns, design scheme, pharmaceutical composition, and additional lipid-lowering agent(s) of the instant claims.
Regarding the APOC3-targeting oligont, WO615 teaches (¶12-13, ¶16, ¶364, Table 7, ¶40, ¶163, ¶191) sequences (including SEQ ID NOs 53-54), modifications, dsRNAs and elements of dsRNA design that make obvious the claimed SEQ ID NOs. WO615 teaches (§Abstract) their dsRNA are for treating lipid diseases including hypercholesterolemia and dyslipidemia.
Regarding the AS strands wherein the 5’ nt is a U mismatch to the target mRNA, Kamola, drawn to principles of rational sequence design for siRNAs, teaches (§Discussion ¶2) benefits of producing siRNAs that comprise A/U at the 5’end of the guide strands.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA of the copending App066 claims with the nucleic acid construct of WO602, the AS strand sequences of WO615, and the teachings of Kamola for the benefit of producing a combination PCSK9- and APOC3-targeting construct according to the various nucleic acid construct designs of WO602 and using it to treat CVD. One would have been motivated to do so with a reasonable expectation of success WO602 teaches (p. 4 25-30) their design schemes improve upon shortcomings of complementary oligonucleotide technologies, such as high product cost, suboptimal efficacy/specificity, low stability, and difficulty of delivery. One would have done so for the benefit of administering an APOC3-inhibiting treatment and one would have been motivated to do so with a reasonable expectation of success because WO602 teaches that their multi-targeting construct can target any two or more genes. It would have been a simple matter to use the AS strands from WO615, optimize them as taught by Kamola, design appropriate sense strands, and then incorporate them into the designs of WO602. It would have been obvious to incorporate the dsRNA of the copending claims because the WO602 teach (cited above) incorporating additional dsRNA.
Therefore the instant claims would have been obvious in view of the dsRNA of the copending App066 claims and the prior art of WO602, WO615, and Kamola.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
International Publication Number WO 2021/185765 (published 23 September 2021),
International Publication Number WO 2016/011123 (published 21 January 2016),
International Publication Number WO 2023/049294 (published 30 March 2023 but PRO was effectively filed on 23 September 2021),
International Publication Number WO 2021/185765 (published 23 September 2021), and
International Publication Number WO 2007/134161 (published 22 November 2007.
All the WO docs cited above disclose PCKS9- or APOC3-targeting oligont.
International Publication Number WO 2017/132669 (published 03 August 2017) teaches branched dsRNA compounds comprising an alternating 2’-OMe and 2’-F pattern.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUTHIE S ARIETI whose telephone number is (571)272-1293. The examiner can normally be reached M-Th 8:30AM-4PM, alternate Fridays 8:30AM-4PM (ET).
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RUTHIE S ARIETI
Examiner
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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