Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims Status
Claims 20-22 is/are cancelled. Claims 1-19 and 23 is/are currently pending and under examination.
Claim Objections
Applicant is advised that should claim 4 be found allowable, claim 5 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Applicants are advised to amend or cancel one of the claims to address this warning.
Claim Rejections - 35 USC § 112
112(d):
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 16 depends on claim 15, which requires an siRNA at least 80% identical to SEQ ID NOs:1-10 or 17-26. However, claim 16 recites that the siRNA may have at least 85% identity with SEQ ID NO:16, a limitation not encompassed by claim 15. Claim 16 thus does not require all of the limitations of claim 15. 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.
112(a):
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.
Written Description:
Claims 1-19, 23 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.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”).
According to the MPEP § 2163, "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 (see i)(A) above), reduction to drawings (see i)(B) above), 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 i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutsch land GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")."
Claim 1 recites an ionizable cationic amino lipid having a pKA of 5.5-7.0 (line 3); however, neither the claims nor the specification provides a description of a structure of an ionizable cationic amino lipid. The genus of ionizable cationic amino lipids having pKas of 5.5-7.0 encompasses an enormous variety of molecules. An artisan would not be able to determine from the present disclosure which species of ionizable cationic amino lipids the applicants were in possession of at the time of filing and whether such species were representative of the entire genus of ionizable cationic amino lipids.
Claim 1 also recites a hydrophilic polymer-lipid conjugate (line 8). However, neither the claims nor the specification provides a description of a structure of a hydrophilic polymer-lipid conjugate. This creates an enormous genus of molecules fitting the description of a hydrophilic polymer-lipid conjugate without a description of any constituent species or species component (e.g., polymers or lipids). An artisan would not be able to determine what hydrophilic polymer-lipid conjugate structures the applicants were in possession of at the time of filing.
Claims 2-14 require the limitations of claim 1, including the presence of a cationic amino lipid and a hydrophilic polymer-lipid conjugate, but do not describe either structure, and as such, are also rejected for lack of written description.
Claims 12-13 require that the siRNA molecule be a conjugate molecule (claim 12) and that the siRNA conjugate comprise a sugar group (claim 13). The genus of siRNA molecule conjugates is enormous, and while the genus of siRNA conjugated to a sugar is more limited, this genus is also enormous. Claim 14 requires that the conjugate molecule be GalNAc. The specification on page 17 recites that the conjugate may be an antibody, a peptide, an amino acid, an aptamer, a phosphate group, a cholesterol moiety, a lipid, a cell-penetrating peptide polymer, a sugar group, or GalNAc. The conjugate being a sugar group is narrower than the conjugate comprising a sugar group. The applicants have described the particular types of molecules that may be conjugated to the siRNA on page 17 of the specification; these structures are not representative of the entire genus of molecules which may be conjugated to an siRNA. Therefore, the applicants have only sufficiently described the conjugate molecules described on page 17 of the specification.
Claims 4-8, 15-18 recite siRNA molecules with 80%-90% sequence identity to SEQ ID NOs:1-10 or 17-26 (in the case of claim 16, siRNA with at least 90% sequence identity to SEQ ID NOs:1-10 or 16-17).
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, SEQ ID NOs:1-10 and 17-26 are the only species whose complete structure is disclosed. While the genus encompasses a large number of variants and molecules that have the same activity of reducing fibrin expression (page 10 describes that the siRNA of the application are targeted to fibrinogen) and the genus encompasses a large number of variants and molecules that have a different structure, the specification does not describe the complete structure of a representative number of species of the large genus of siRNA having less than 100% identity with SEQ ID NOs:1-10 and 16-26 or functional equivalents thereof. Additionally, the specification does not describe the complete structure of a representative number of species of the large genus of modified siRNA. Furthermore, the art at the time of filing taught that mismatches between siRNA and target sequences, depending on the number and location of the mismatches, could eliminate any RNAi interference activity (see Amarzguioui, 2003). Thus, without a description of specific mutations permissible which do not eliminate the desired activity of the siRNA, an artisan would not be able to determine that the applicants were in possession of siRNA less than 100% identical to SEQ ID NOs:1-10 or 16-26 having the function of reducing fibrin expression.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only other identifying characteristic is that the siRNA target fibrinogen alpha chain mRNA (page 10 of the specification). Such a functional limitation cannot be an identifying characteristic for the claimed diverse genus of molecules since by Applicant’s definition of the genus of variant siRNA or functional equivalent thereof, all members of the claimed genus will have that characteristic. Additionally, the prior art teaches that siRNA comprising one or more mismatches may no longer exhibit RNA interference activity (Amarzguioui, 2003). Further, no identifying characteristics of the variant siRNA are disclosed.
The inventions of claims 19 and 23 require the use of the invention of claims 15 and therefore are likewise rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement.
Scope of Enablement:
Claim 23 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of patients having thrombotic or acute inflammation disorders, known in the art to be treated by therapies which reduce fibrin or fibrinogen expression and evidenced in the disclosure using murine models, does not reasonably provide enablement for methods of treating any fibrin- or fibrinogen-dependent disorder, as this encompasses disorders which are not known to be treated by therapies which reduce fibrin or fibrinogen expression and disorders caused by reduced fibrin or fibrinogen expression. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims:
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method is that it would treat a patient having any fibrin- or fibrinogen-dependent disorder, including disorders caused by reduced fibrin or fibrinogen expression or any other disorder dependent on fibrin or fibrinogen and which is not known in the art to be treatable using a therapy which reduces fibrin or fibrinogen expression. A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The amount of direction provided by the inventor and the level of predictability in the art:
The specification teaches that “fibrion(ogen)-dependent diseases or disorders, include, but are not limited to: hyperfibrinogenemia, acute inflammation after microbial and/or viral infections (e.g., sepsis, COVID-19), chronic inflammation (e.g., associated with increasing age and in diseases such as obesity, arthritis, diabetes, and the like); thrombosis, including thrombosis associated with cancer and trauma; thromboinflammation (thrombosis associated with increased inflammation); cardiovascular disease; and cancer growth, progression, and metastasis” (page 10). The art at the time of filing provided enabling guidance for methods of treating thrombotic and inflammatory diseases by reducing fibrinogen levels using defibrinogenating agents like ancrod and thrombolytics (Soutar, 1993; Adams, 2007). The art at the time of filing taught that therapeutics which decrease fibrinogen expression, such as Ancrod, were not capable of treating cancer (Calderon, 2014, see page 2), and that certain fibrin-dependent diseases were caused by reduced fibrin or fibrinogen expression and should be treated by increasing fibrin expression (Machin, 2018; Gaule, 2021). As such, a therapy which reduces fibrin(ogen) expression was known in the art to not be capable of treating a number of diseases representative of the entire genus of diseases associated with or dependent on fibrin(ogen) expression. The specification as filed does not provide guidance that overcomes this unpredictability within the art.
The existence of working examples:
What is enabled by the working examples is narrow in comparison to the breadth of the claims: The specification discloses in vivo experiments wherein the siRNA is administered to mice (pages 22-33). Reduced clotting was observed in wild type mice (pages 28-30). Thrombosis was found to decrease after induction of IVC stasis (page 30). Attenuation of acute phase response in a mouse model of endotoxemia was found (pages 30-31). Peritonitis was ameliorated in plasminogen-deficient mice (pages 31-32). Macrometastases, but not micrometastases, were reduced in mice injected with Lewis Lung Carcinoma cells (pages 26, 32-33; Fig. 7).
The quantity of experimentation needed to make or use the invention:
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is in vivo treatment of a patient having any fibrin(ogen)-dependent disorder (including disorders not known to be treated by reduction of fibrin(ogen) expression or are caused by or associated with reduced fibrin(ogen) expression), a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials or in animal models predictive of treatment of a representative number of diseases dependent on fibrin(ogen) expression or activity, which are not known to be treated by reduction of fibrin(ogen) expression or which are known to be caused by or associated with reduced fibrin(ogen) expression, in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating any CNS disorder or neurodegenerative disease. Therefore, Claim 23 is rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
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) 15-19, 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhao (WO2013130868A1, of record).
Regarding claims 15-18, Zhao teaches an siRNA targeting a human fibrinogen nucleic acid (SEQ ID NOs:1-3) and consisting of 12-30 linked nucleosides (claims 28-30; pages 19-20, 24, 31). While Zhao only provides siRNA sequences targeting murine fibrinogen (pages 69-71), Zhao provides the target human sequences and teaches any siRNA sequence of 12-30 nucleosides which targets human fibrinogen sequences of SEQ ID NOs:1-3. Thus, Zhao renders obvious any siRNA 12-30 nucleosides long which is at least 90%, 95%, or 100% complementary to, or at least 70%-100% identical to, an equal-length sequence within SEQ ID NOs:1-3. This encompasses instant SEQ ID NOs:1-10 and 17-26 (page 42) (see alignment below between instant SEQ ID NO:2 and Zhao SEQ ID NO:1, wherein “/c” indicates complementarity) (SEQ ID NOs: 1-10, 17-26 are each at least 90% identical or complementary to Zhao SEQ ID NO:1). Zhao thus renders obvious siRNA at least 90% identical to instant SEQ ID NOs:1-10 and 17-26.
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Regarding claim 19, Zhao teaches pharmaceutical compositions comprising the siRNA (page 57).
Regarding claim 23, Zhao teaches a method of treating a fibrinogen-dependent disease (fibrosis or DMD) comprising administering the siRNA (claims 2-4).
Claim(s) 1-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhao (WO2013130868A1, of record) in view of Patel (US 20200129445 A1, of record), as evidenced by BroadPharm (2026).
Regarding claims 1-2, Zhao teaches an siRNA targeting human fibrinogen alpha chain mRNA (claims 28-30; pages 19-20, 24, 31; SEQ ID NO: 1).
Regarding claim 3, Zhao teaches that the siRNA comprises modified or unmodified nucleotides, wherein the modified nucleotides are methylated (claims 24-25, 40-41).
Regarding claims 4-8, Zhao teaches an siRNA targeting a human fibrinogen nucleic acid (SEQ ID NOs:1-3) and consisting of 12-30 linked nucleosides (claims 28-30; pages 19-20, 24, 31). While Zhao only provides siRNA sequences targeting murine fibrinogen (pages 69-71), Zhao provides the target human sequences and teaches any siRNA sequence of 12-30 nucleosides which targets and is at least 90%, 95%, or 100% complementary or identical to human fibrinogen sequences of SEQ ID NOs:1-3. Thus, Zhao renders obvious any siRNA 12-30 nucleosides long which is at least 90%, 95%, or 100% complementary to, or at least 70%-100% identical to, an equal-length sequence within SEQ ID NOs:1-3. This encompasses instant SEQ ID NOs:1-10 and 17-26 (page 42) (see alignment below between instant SEQ ID NO:2 and Zhao SEQ ID NO:1, wherein “/c” indicates complementarity) (SEQ ID NOs: 1-10, 17-26 are each at least 90% identical or complementary to Zhao SEQ ID NO:1). Zhao thus renders obvious siRNA at least 90% identical to instant SEQ ID NOs:1-10 and 17-26.
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Regarding claims 9-11, Zhao teaches that the siRNA is 12-30 nucleotides long (claim 30).
Regarding claims 12-13, Zhao teaches that the siRNA may be conjugated to a sugar moiety (pages 58-59).
However, Zhao does not teach that the siRNA is encapsulated in a lipid nanoparticle.
Patel teaches that siRNA should be encapsulated in lipid nanoparticles for delivery.
Regarding claim 1, Patel teaches lipid nanoparticles for encapsulating siRNA (claim 45), wherein the lipid nanoparticle comprises: 30%-60% cationic ionizable amino lipid (claims 38-41); a phospholipid (claims 38-40); two sterols (claims 38-40); and a PEG lipid conjugate (claims 38-40). At least some of these cationic ionizable amino lipids have a pKa between 5.5 and 7.0 (see BroadPharm, 2026, which teaches that DLin-DMA has a pKa of 6.0).
Patel teaches that “Lipid-containing nanoparticle compositions, liposomes, and lipoplexes have proven effective as transport vehicles into cells and/or intracellular compartments for biologically active substances such as small molecule drugs, proteins, and nucleic acids” (paragraph [0004]). It would have been obvious to an artisan at the time of filing that in order to deliver the siRNA of Zhao to cells, as required by the methods of Zhao, the siRNA should be formulated such that delivery to cells would be facilitated. It thus would have been obvious to use known delivery vehicles, such as the lipid nanoparticles taught by Patel, for formulating the siRNA of Zhao for delivery to cells.
Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhao (WO2013130868A1, of record) in view of Patel (US 20200129445 A1, of record), as evidenced by BroadPharm (2026) as applied to claims 1 and 12-13 above, and further in view of Springer (2018).
The limitations of claims 1 and 12-13 are rendered obvious by the teachings of Zhao and Patel, as discussed above.
However, Zhao and Patel do not teach that an siRNA should be conjugated to GalNAc.
Springer teaches that siRNA targeted to liver tissue should be conjugated to GalNAc.
Regarding claim 14, Springer teaches that conjugation of siRNA to GalNAc increases efficiency of siRNA delivery to liver tissue (Abstract).
Regarding claim 14, Zhao teaches that the siRNA should be delivered to liver tissue (claim 4). As Zhao teaches that the siRNA should be delivered to the liver, it would have been obvious to an artisan at the time of filing that modifications to the siRNA or delivery mechanisms for the siRNA which were known in the art to enhance delivery to or uptake by liver tissues should be used in order to enhance siRNA delivery to or uptake by liver tissue. Springer teaches that GalNAc conjugation to siRNA enhances uptake of the siRNA by liver cells, and thus it would have been obvious to an artisan at the time of filing that the siRNA of Zhao should be conjugated to GalNAc.
Conclusion
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/AFRICA M MCLEOD/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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