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 .
Information Disclosure Statement
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.
Drawings
The drawings are objected to for the following reasons:
37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.”
In the current case, the view numbers for the partial views for Figures 1B, 2A, 2B, 3A, and 3B that appear on several sheets are followed by "Cont’d" instead of a capital letter such as FIG. 1A, FIG. 1B, etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-15 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.
Regarding claim 1, the claim recites “a disease, disorder, or conditional associated with undesirable proprotein convertase subtilisin/kexin type 9 (PCSK9) gene expression” in lines 1-2 of the claim. The instant specification does not describe a standard by which one can determine when expression of PCSK9 is “undesirable”. Further, as evidenced by a review study concerned with expression of PCSK9 and the relationship of the expression with inflammatory disease, Momtazi-Borojeni (European Heart Journal-Cardiovascular Pharmacotherapy 5.4 (2019): 237-245), the correlation of PCSK9 expression with disease selected from acute coronary syndrome and coronary artery disease was variable (pg. 239; see Table 1). Thus, the prior art demonstrates that an “undesirable” level of PCSK9 is variable with regard to a particular disease that is indicative of the elevated PCSK9 expression. Accordingly, the claimed “undesirable” level of PCSK9 expression is unclear because neither the specification nor the prior art teaches a single standard by which one can determine when expression of PCSK9 is “undesirable”.
Regarding claims 2-15, as the claims are ultimately dependent on claim 1 and do not rectify the 35 USC 112(b) rejection above, the claims are also rejected under 35 USC 112(b).
Regarding claims 4 and 8, the claims recite the phrase “the galactosyl-conjugated LNP” in line 2 of the claims. It is not clear that the sugar or monosaccharide of claim 1 is limited to a galactosyl moiety because, for example, the monosaccharide could be fructose, fructose or mannose. It would be remedial to amend the phrase “the galactosyl-conjugated LNP” to recite “a galactosyl-conjugated LNP.”
Regarding claim 15, the claim recites the phrase “a 3-hydroxy-3-methylglytaryl coenzyme A inhibitor (e.g., a statin)” in line 8 of the claim. It is not clear whether the recitation of “a statin” is limiting or if it is merely exemplary.
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 1-15 are 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 treating a subject with a cardiovascular disease, the method comprising administering to the subject an effective amount of a composition comprising a sugar-conjugated lipid nanoparticle (LNP) and an active agent encapsulated therein, wherein the active agent is selected from the group consisting of an siRNA molecule that comprises the sense strand of SEQ ID NO: 1 and the antisense strand of SEQ ID NO:2 to target PCSK9 mRNA, and an siRNA molecule that comprises the sense strand of SEQ ID NO: 7 and the antisense strand of SEQ ID NO: 8 to target PSCK9 mRNA, and wherein the active agent modulates proprotein convertase subtilisin/kexin type 9 (PCSK+) gene expression to thereby treat cardiovascular disease, does not reasonably provide enablement for utilizing any active agent to treat and/or prevent any disease, disorder, or condition associated with PCSK9, or for absolutely preventing any disease, disorder, or condition associated with PCSK9. 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. They include (1 the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Regarding claim 1, the claim requires treating and/or preventing a disease, disorder or condition associated with undesirable proprotein convertase subtilisin/kexin type 9 (PCSK9) gene expression via the administration of a sugar-coated LNP and an active agent encapsulated therein, wherein the active agent modulates the PCSK9 gene expression to thereby treat and/or prevent the disease, disorder or condition. It is noted that the term “modulate” encompasses both inhibiting and stimulating an activity, function, or process (Instant specification; pg. 23).
The state of the art, the unpredictability of the art, and the relative skill of the ordinary artisan
It is well established in the prior art that there are specific PCSK9 inhibitors that were known in the art to be able to inhibit PCSK9 gene expression in order to treat cardiovascular diseases. However, the prior art further teaches that the inhibitors must be of a specific structure, targeted to the liver, and that the diseases associated with PCSK9 gene expression were limited to cardiovascular diseases.
Rosenson ("The evolving future of PCSK9 inhibitors." Journal of the American College of Cardiology 72.3 (2018): 314-329) is directed towards a review concerned with PCSK9 inhibitors (Abstract). Rosenson teaches that inhibiting PCSK9 results in a lower level of LDL-C and results in the reduction of atherosclerotic cardiovascular disease events selected from acute coronary syndrome, multivessel coronary artery disease, and peripheral arterial disease (Abstract). Rosenson teaches that both monoclonal antibodies and siRNA molecules delivered to the liver were able to block either plasma PCSK9 or PCSK9 transcription (pg. 319; see Figure 2).
Therefore, a review study concerned with the use of PCSK9 inhibitors demonstrates that it would have been unpredictable to utilize active agents, not limited by structure, to developed in order to increase or decrease PCSK9 expression for treatment of diseases other than cardiovascular disease. Further, although Rosenson does provide evidence that utilizing mAB and siRNA to decrease PCSK9 gene expression was known in the art, Rosenson does not provide evidenced that active agents, not limited by structure, were able to increase or decrease the expression level of PCSK9 in a subject in order to prevent a disease associated with PCSK9 gene expression, as currently claimed.
Further, it is well established in the art that active agents, selected from siRNA, utilized to treat a disease must be of a specific structure in order to treat a disease of interest. Ding ( "Cross-talk between LOX-1 and PCSK9 in vascular tissues." Cardiovascular research 107.4 (2015): 556-567) is directed towards a study concerned with how LOX-1 and PCSK9 interact in vascular tissues (Abstract). Ding teaches the use of siRNA molecules that can target LOX-1 in order to synergistically reduce the expression of both LOX-1 and PCSK9 (pg. 560). Ding teaches that the siRNA molecules must comprise a specific sequence in order to successfully target LOX-1 mRNA in order to reduce the expression of PCSK9 (pg. 560). Ding teaches that control siRNA molecules with a scrambled sequence (pg. 557) were unable to target LOX-1 (pg. 561; see Figure 4).
Therefore, the prior art teaches that utilizing any first or second active agent to treat and/or prevent any disease, disorder, or condition associated with PCSK9, as currently claimed, is unpredictable because the prior art teaches that the structure of an first and second active agents must be specific and can only be utilized in a method of treating a specific disease through specific structure interactions. In addition, the skill of those in the relative art is high, but still, given the state and unpredictability of the art, undue experimentation would be required to determine if any first or second active agent can be utilized to treat and/or prevent any disease, disorder, or condition associated with PCSK9. Therefore, utilizing any first or second active agent to treat and/or prevent any disease, disorder, or condition associated with PCSK9 cannot be predictably accomplished, as presently claimed.
Amount of experimentation required and the direction or guidance presented
In order to determine how to act, one of ordinary skill in the art would have to practice undue experimentation to determine if any active agent, not limited by structure, can be utilized to treat and/or prevent any disease, disorder, or condition, so long as it is associated with PCSK9. Even if the method was performed as claimed, there is no evidence in the prior art nor the instant specification that any active agent, not limited by any structure, can be utilized to treat and/or prevent any disease, disorder, or condition, so long as it is associated with PCSK9. The mere ability to administer a sugar-coated LNP to deliver a single siRNA molecule that is defined by a specific structure in order to knockdown specific PCSK9 mRNA, as taught in the specification (pg. 53, 56-57; see Figures 7-9 and Table 8), is not representative of the ability to predictably use the invention as claimed. In addition, the specification, as filed, fails to provide any particular direction or guidance which resolves the known unpredictability in the art associated with utilizing any active agent to treat and/or prevent any disease, disorder, or condition associated with PCSK9 as currently claimed.
Nature of the invention, the presence or absence of working examples, and the breadth of the claims
It is noted that the instant specification teaches that the term “prevent” need not be absolute (pg. 25). While the specification does provide support for utilizing LNPs comprising two possible siRNA molecules selected from the group consisting of a sense strand of SEQ ID NO: 1 and an antisense strand of SEQ ID NO: 2 (pg. 53) and a sense strand of SEQ ID NO: 7 and an antisense strand of SEQ ID NO: 8 (pg. 56), it fails to disclose how to utilize any active agent to treat and/or prevent any disease, disorder, or condition associated with PCSK9 as currently claimed. The two siRNA molecules disclosed were able to target and knockdown specific PCSK9 mRNA that was limited to a specific structure in a dose dependent manner (pg. 53; see Figures 7-9). Because the claimed invention claims that the active agent, not limited by any structure, can be utilized to treat and/or prevent any disease, disorder, or condition, so long as it is associated with PCSK9, the specification does not provide any disclosure to enable the claims over their full scope. Therefore, the claim is not enabled commensurate in scope with the claimed invention.
Regarding claims 2-12, as the claims are ultimately dependent on claim 1 and do not rectify the 35 USC 112(a) enablement rejection above, the claims are also rejected under 35 USC 112(a).
Regarding claims 13-15, the claims identify broad classes of diseases, disorders, or conditions, such as inflammatory disease or cardiovascular disease. The broadly claimed genera of diseases, disorders, or conditions in the claims are not enabled for the same reasons applied above to instant claim 1.
Claims 1-15 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.
Regarding claim 1, the claim is broadly drawn towards a method of treating and/or preventing a disease, disorder or condition associated with undesirable proprotein convertase subtilisin/kexin type 9 gene expression via the administration of a sugar-coated LNP and an active agent encapsulated therein, wherein the active agent modulates the PCSK9 gene expression to thereby treat and/or prevent the disease, disorder or condition.
Accordingly, the claim is interpreted as claiming a genus of active agents that have the function of modulating the expression of a PCSK9 gene to treat and/or prevent a disease, disorder or condition associated with undesirable PCSK9 gene expression. The claim requires the provision a genus of agents defined solely by function.
Regarding claim 14, the claim is drawn towards a broadly claimed second active agent that is appropriate for treating the disease, disorder, or condition.
Accordingly, the claim is interpreted as claiming a genus of second active agents, not limited by structure, that can treat the disease, disorder or condition associated with undesirable PCSK9 gene expression. The claim requires the provision a genus of second agents defined solely by function.
Regarding claim 15, the claim is drawn towards a broadly claimed second active agent that is appropriate for treating a specific disease, disorder or condition. Regarding part (i) of the claim, the claim recites that the disease is an inflammatory disease and the second active agent is an anti-inflammatory agent, optionally a nonsteroidal anti-inflammatory drug (NSAID), a steroid, acetaminophen or other COX-3 inhibitor, a 5-lipoxygenase inhibitor, a leukotriene receptor antagonist, a leukotriene A4 hydrolase inhibitor, an antihistaminic, a histamine 2 receptor antagonist, a phosphodiesterase-4 antagonist, a cytokine antagonist, a CD44 antagonist, an antineoplastic agent, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor (e.g., a statin), an estrogen, an androgen, an antiplatelet agent, an antidepressant, a Helicobacter pylori inhibitor, a proton pump inhibitor, a thiazolidinedione, or a dual-action compound.
Accordingly, part (i) of the claim is interpreted as being directed towards a method of treating a genus of inflammatory diseases via the use of many different second agents that are defined solely by function and do not require an explicit structure.
Regarding part (ii) of claim 15, the claim recites that the disease is a cardiovascular disease, disorder, or condition, optionally atherosclerosis, and the second active agent is an acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, including but not limited to a selective inhibitor of ACAT-1, ACAT-2 as well as dual inhibitors of ACAT-1 and ACAT-2; an alpha-adrenergic blocking drug (alpha-blocker), an alpha/beta blocker, an angiotensin-converting enzyme (ACE) inhibitor, an aldosterone antagonist, an angiotensin II receptor antagonist, an anti-arrhythmic, an anticoagulant, an antiplatelet agent, an apolipoprotein A-1 (apoA-1) mimetic, a beta-blocker, a bile acid sequestrant, a calcium-channel blocker, an ApoB cholesteryl ester transfer protein (CETP) inhibitor, a cholesterol absorption inhibitor, a diuretic, a dyslipidemia agent, an endothelin receptor antagonist, a fibrate, a 3-hydroxy-3-methyl-glutaryl- coenzyme A (HMG-CoA) reductase inhibitor, an LCAT activator, an LDL receptor inducer, a lipase inhibitor, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, a microsomal triglyceride transfer protein (MTP) inhibitor, a platelet aggregation inhibitor, a PPAR agonist and/or activator, optionally a PPARy agonist, PPARa agonist, and/or a PPAR dual a/y agonists, a second PCSK9 antisense nucleic acid or RNAi, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, a thrombolytic, a thyroid receptor beta activator, or any combination thereof.
Accordingly, part (ii) of the claim is interpreted as being directed towards a method of treating a genus of cardiovascular diseases via the use of many different second agents that are defined solely by function and do not require an explicit structure.
Regarding part (iii) of claim 15, the claim recites that the disease is a cardiovascular disease, disorder, or condition, and the second active agent targets a vasculature cell, a muscle cell, a fibroblast, and/or an endothelial cell, optionally a vascular endothelial cell, wherein the second active agent binds to a target selected from the group consisting of LOX-1, a selectin, optionally a P- selectin or an E-selectin, an integrins, and a neuropilin.
Accordingly, part (iii) of the claim is interpreted as being directed towards a method of treating a genus of cardiovascular diseases via the use of many different second agents that are defined solely by function and do not require an explicit structure.
Regarding part (iv) of claim 15, the claim recites that the disease is sepsis, septic shock, or cytokine storm and the second active agent is an antibiotic, a complement inhibitor, optionally a complement inhibitor selected from the group consisting of a C5a inhibitor, a C5aR inhibitor, a C3 inhibitor, optionally wherein the C3 inhibitor is Compstatin, a Compstatin analog, a Compstatin peptidomimetic, or a Compstatin derivative, a factor D inhibitor, a factor B inhibitor, a C4 inhibitor, a C1q inhibitor, or any combination thereof.
Accordingly, part (iv) of the claim is interpreted as being directed towards a method of treating sepsis, septic shock, or cytokine storm via the use of many different second agents that are defined solely by function and do not require an explicit structure.
The instant specification does not provide support for the use of a genus of structures of active agents or second active agents that can perform the claimed function, and the prior art provides evidence that active agents must comprise a specific structure in order to perform the claimed function and that utilizing any active agents, not limited by structure, is unpredictable.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would leave one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP 2163. A claimed genus may be satisfied through sufficient descriptions of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with known or disclosed correlation between function and structure. MPEP 2163(3)a(II). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure, and (d) representative number of samples.
As the claims currently recite, as described above, the claim is directed towards a method of treating and/or preventing a disease, disorder or condition associated with undesirable proprotein convertase subtilisin/kexin type 9 gene expression via the administration of a sugar-coated LNP and an active agent encapsulated therein, wherein the active agent modulates the PCSK9 gene expression to thereby treat and/or prevent the disease, disorder or condition. While claiming a genus of structures (i.e., first and second active agents not limited by structure) by a function (i.e., the claimed modulation of PCSK9 gene expression) is not prohibited, there must be a sufficient structure-function relationship described in the specification such that the claimed genus was represented by a representative number of species or the teachings of the specification, or, the prior art can be used to support a well-known structure-function relationship.
In the instant case, the instant specification does not provide support that the broadly claimed first or second active agents are able to perform the claimed function. Further, the prior art demonstrates that the use of first and second active agents to perform the claimed function is sequence specific and that utilizing any active agent to perform the claimed function is unpredictable.
Working Examples
With regard to working examples, the specification provides little evidence on the possession of a sufficient number of species which are encompassed by the entirety of the claimed genus.
MPEP 2163 teaches that “for some arts, there is an inverse correlation between the level of skill and knowledge in the art and the specificity of disclosure necessary to satisfy the written description requirement. Information which is well known in the art need not be described in detail in the specification. See, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986). However, sufficient information must be provided to show that the inventor had possession of the invention as claimed [emphasis added].”
In the instant case, regarding claim 1, the specification teaches the use of LNPs comprising two possible siRNA molecules selected from the group consisting of a sense strand of SEQ ID NO: 1 and an antisense strand of SEQ ID NO: 2 (pg. 53) and a sense strand of SEQ ID NO: 7 and an antisense strand of SEQ ID NO: 8 (pg. 56) that can target PCSK9 mRNA in order to modulate gene expression (pg. 53, 56-57; see Table 8). The instant specification teaches the use of a two siRNA sequences that can target PCSK9 (pg. 53, 56-57), and siRNA sequences that can target HDAC2, GAPDH, and NRF2 (pg. 56-57).
However, when taken as a whole, the set of siRNA molecules present in the specification is not representative of the claimed genus as a whole because the claimed genus broadly encompasses any active agent of any structure that can performed the claimed function of modulating PCSK9 gene expression. Therefore, the instantly claimed genus of active agents present in claim 1 is not adequately described in the specification as being able to facilitate a modulation of PCSK9 gene expression.
Thus, the instant specification does not provide written description for the entirety of the claimed method comprising any active agent of any structure that can modulate PCSK gene expression (see Claim 1).
Further, regarding claims 14-15, while the instant specification broadly contemplates the use of a second agent selected from those in the claim (pg. 5-6), the instant specification provides no working examples of the use of a second active agent, not defined by structure, that can be utilized to treat and/or prevent a disease selected from (i) an inflammatory disease, (ii)-(iii) a cardiovascular disease, or (iv) sepsis, septic shock, or cytokine storm. Further, of the genera of second active agents recited in the claim that do not recite an explicit structure and the instant specification does not provide any disclosure of species of the claimed genera of second agents nor what the structures of the species of second agents might comprise in order to be utilized to treat and/or prevent the broadly claimed diseases.
Prior Art
Regarding the state of the prior art, the prior art demonstrates that first and second active agents utilized to treat a disease through the modulation of PCSK9 gene expression must be of a specific structure in order to perform the claimed function.
Rosenson ("The evolving future of PCSK9 inhibitors." Journal of the American College of Cardiology 72.3 (2018): 314-329) is directed towards a review concerned with PCSK9 inhibitors (Abstract). Rosenson teaches that inhibiting PCSK9 results in a lower level of LDL-C and results in the reduction of atherosclerotic cardiovascular disease events selected from acute coronary syndrome, multivessel coronary artery disease, and peripheral arterial disease (Abstract). Rosenson teaches that both monoclonal antibodies and siRNA molecules delivered to the liver were able to block either plasma PCSK9 or PCSK9 transcription (pg. 319; see Figure 2). Further Rosenson teaches that second active agents selected from statins and inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase may be administered alongside the PCSK9 inhibitors in order to synergistically reduce LDL levels in a subject alongside the reduction of PCSK9 in order to treat cardiovascular diseases (pg. 315).
Therefore, a review study concerned with the use of PCSK9 inhibitors demonstrates that it would have been unpredictable to utilize first or second active agents, not limited by structure, in order to increase or decrease PCSK9 expression for treatment of diseases other than cardiovascular disease. Although Rosenson does provide evidence that utilizing mAB and siRNA to decrease PCSK9 gene expression was known in the art, Rosenson does not provide evidenced that active agents, not limited by structure, were able to increase or decrease the expression level of PCSK9 in a subject in order to prevent a disease associated with PCSK9 gene expression, as currently claimed. Further, although Rosenson does teach that statins and inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase may be administered alongside PCSK9 inhibitors to synergistically reduce LDL levels in a subject, Rosenson does not provide evidenced that second active agents, not limited by structure, were able to increase or decrease the expression level of PCSK9 in a subject in order to prevent a disease associated with PCSK9 gene expression, as currently claimed
Further, Ding ( "Cross-talk between LOX-1 and PCSK9 in vascular tissues." Cardiovascular research 107.4 (2015): 556-567), is directed towards a study concerned with how LOX-1 and PCSK9 interact in vascular tissues (Abstract). Ding teaches the use of siRNA molecules that can target LOX-1 in order to synergistically reduce the expression of both LOX-1 and PCSK9 (pg. 560). Ding teaches that the siRNA molecules must comprise a specific sequence in order to successfully target LOX-1 mRNA in order to reduce the expression of PCSK9 (pg. 560). Ding teaches that control siRNA molecules with a scrambled sequence (pg. 557) were unable to target LOX-1 in order to reduce PCSK9 gene expression (pg. 561; see Figure 4).
Thus, the prior art shows that prior to the effective filing date of the claimed invention it was not predictable that a broad set of first or second active agents, not limited by structure, could be utilized to modulate the expression of PCSK9. Rather, the prior art shows that the successful modulation of PCSK9 is determinant on the specific structure of active agents in order to perform the claimed function. Further, the prior art provides evidence that a large amount of experimentation was required in order to determine if a specific active agent was able to modulate the expression of PCSK9.
Conclusion
The specification does not identify a representative number of species of the broadly claimed set of first or second active agents that possess the claimed function of modulating PCSK9 gene expression. Further, the prior art shows that prior to the effective filing date of the claimed invention that determining the ability for a first or second active agent to modulate the expression of PCSK9 is structure-dependent and that it is unpredictable to utilize any first or second active agent, not limited by structure, to perform the claimed function.
Therefore, a person of ordinary skill in the art would not have concluded that Applicant was in possession of the invention as claimed. Thus, claims 1 and 14-15 are rejected under 35 U.S.C. 112(a).
Regarding claims 2-5 and 8-15, as the claims are ultimately dependent on claim 1 and do not rectify the 35 USC 112(a) rejection above, the claims are also rejected under 35 USC 112(a).
Regarding claim 6, while the claim limits the active agent to a nucleic acid, it does not require the nucleic acid to directly modulate expression of PCSK9. Further, the instant specification teaches that the term nucleic acid encompasses RNA as well as ssDNA, dsDNA, cDNA, and coding nucleic acids where those coding nucleic acids could potentially act on pathways to modulate PCSK9 (pg. 23-24). Therefore, claim 6 claims a very large genus of nucleic acid molecules that are not adequately described in the instant specification as discussed above and applied to claim 1.
Regarding claim 7, while the claim limits the active agent to an inhibitory nucleic acid that inhibits the biological activity of a PCSK9 gene product, the claimed inhibitory nucleic acid is not limited by structure and possesses a function of inhibiting a PCSK9 gene product. Accordingly, claim 7 claims a large genus of siRNA molecules that can inhibit the biological activity of a PCSK9 gene product that is itself not limited by structure. Therefore, claim 7 claims a very large genus of inhibitory nucleic acid molecules that are not adequately described in the instant specification as discussed above and applied to claim 1.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-9, 11, and 13-14 is/are rejected under 35 U.S.C. 102(a)(1) and 102 (a)(2) as being anticipated by Rajeev (PG Pub No. US 2021/0299261 A1, published 30 September 2021, filed 4 March 2021).
Regarding claim 1, Rajeev is directed towards an invention concerned with methods for targeted delivery of therapeutic agents for modifying expression and function of target genes, including proteins involved in lipid and cholesterol metabolism such as PCSK9 (Abstract). Rajeev teaches the use of an LNP composition that comprises a payload ([0408]). Rajeev teaches that the LNP may comprise receptor targeting conjugates selected from GalNAc (i.e., the LNP may be a sugar-conjugated LNP) ([0271]). Rajeev teaches that the payload may be a therapeutic agent selected from an siRNA molecule ([0408]). Rajeev teaches that the siRNA may be directed towards a target DNA or RNA sequence ([0465]). Rajeev teaches that the target sequence may be within a target gene of a gene associated with coronary disease, selected from PCSK9 ([0032], [0037]).
Regarding claim 2, Rajeev teaches that the sugar may be GalNAc ([0271]).
Regarding claim 3, Rajeev teaches that the targeting moiety may comprise one or more galactose moieties (i.e., the LNP may be a galactosyl-conjugated LNP) ([0032]). Rajeev teaches that the LNP may comprise 10 mol% cholesterol ([0025]).
Regarding claim 4, Rajeev teaches that the LNP may comprise cholesterol (i.e., a hydrolysable ionizable lipid) ([0383]).
Regarding claim 5, Rajeev teaches that GalNAc moieties (i.e., one or more galactosyl moieties) can be attached to different sterols, including cholesterol, through different PEG spacers (i.e., cholesterol can be bioconjugated to the GalNAc moiety) ([0272]).
Regarding claim 6, Rajeev teaches that the payload may be a therapeutic agent selected from an siRNA molecule ([0408]).
Regarding claim 7, Rajeev teaches that the siRNA may be directed towards a target DNA or RNA sequence ([0465]). Rajeev teaches that the target sequence may be within a target gene of a gene associated with coronary disease, selected from PCSK9 (i.e., the siRNA may be directed towards a gene product selected from PCSK9 mRNA and inhibit its biological activity) ([0032], [0037])
Regarding claim 8, Rajeev teaches that the targeting moiety recognized and binds a target cell of interest ([0205]).
Regarding claim 9, the claimed “ratiometric combination” is interpreted as encompassing a combination of ionizable lipids at any ratio. Rajeev teaches that the LNP may comprise one or more ionizable lipids (i.e., Rajeev teaches that the LNP may comprise a ratiometric combination of ionizable lipids) ([0402], [0404]).
Regarding claim 11, Rajeev teaches that GalNAc moieties (i.e., one or more galactosyl moieties) can be attached to different sterols, including cholesterol, through different PEG spacers (i.e., the LNP may comprise a cholesterol conjugated to a sugar moiety through the use of a PEG moiety) ([0272]).
Regarding claim 13, Rajeev teaches that the method may be utilized to treat a cardiovascular disease ([0030]).
Regarding claim 14, Rajeev teaches that two or more active agents may be conjugated to a single targeting agent ([0202]).
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) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rajeev (PG Pub No. US 2021/0299261 A1, published 30 September 2021, filed 4 March 2021) as applied to claims 1-9, 11, and 13-14 above, and further in view of Zhang ("Lipids and lipid derivatives for RNA delivery." Chemical reviews 121.20 (2021): 12181-12277).
Regarding claim 10, Rajeev anticipates claims 1-9, 11, and 13-14 as described above. Rajeev teaches that the LNP may comprise one or more ionizable lipids selected from Dlin-MC3-DMA (i.e., Rajeev teaches that the LNP may comprise a combination of ionizable lipids) ([0402], [0404]).
It is noted that the instant specification teaches that the claimed “ratiometric combination of ionizable lipids with a specific dissociation value of between about 6.05 and about 6.44” encompasses a combination of a DLinMc3DMA lipid, an ALC-0315 lipid, and an SM-102 lipid (Instant specification; pg. 51).
Rajeev does not teach or suggest that the LNP further comprises a ratiometric combination of ionizable lipids that have a specific dissociation constant value of between about 6.05 and about 6.44 (Claim 10).
However, one of ordinary skill in the art would have considered the teachings of Zhang as both references are common fields of endeavor pertaining to the use of ionizable lipids in lipid nanoparticles.
Zhang is directed towards a review study concerned with lipids and lipid derivatives for RNA delivery (Abstract). Zhang teaches that LNPs comprising GalNAc clusters are targeted to liver hepatocytes (pg. 12247). Zhang teaches that both ALC-0315 and SM-102 were known ionizable lipids that could be utilized within LNPs and kept shelf stable for as long as three years (pg. 12216-12217). Zhang teaches that LNPs comprising either ALC-0315 or SM-102 were able to be utilized to express an mRNA encoding a reporter luciferase gene (pg. 12214). Zhang teaches that Dlin-MC3-DMA, ALC-0315, and SM-102-base lipid nanoparticles have been approved by the FDA for clinical use in the delivery of nucleic acids of interest (pg. 12252).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute at least two ionizable lipids of Rajeev for an ALC-0315 lipid and an SM-102 lipid, as described by Zhang. A person of ordinary skill in the art would have had a reasonable expectation of success because Rajeev teaches that two or more ionizable lipids may be present within the LNP while Zhang teaches that both ALC-0315 and SM-102 were known ionizable lipid that could be conjugated to an LNP in order to successfully deliver a nucleic acid of interest to a target cell and stabilize the LNP comprising a nucleic acid.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rajeev (PG Pub No. US 2021/0299261 A1, published 30 September 2021, filed 4 March 2021) as applied to claims 1-9, 11, and 13-14 above, and further in view of Mui ( "Influence of polyethylene glycol lipid desorption rates on pharmacokinetics and pharmacodynamics of siRNA lipid nanoparticles." Molecular Therapy Nucleic Acids 2 (2013)).
Regarding claim 12, Rajeev anticipates claims 1-9, 11, and 13-14 above.
Rajeev does not teach or suggest that the PEG moiety comprises a chain length of 1-15 carbons (Claim 12).
However, one of ordinary skill in the art would have considered the teachings of Mui as both references are common fields of endeavor pertaining to the use of PEG moieties for the delivery of siRNA.
Mui is directed towards a study concerned with the influence that differing lengths of PEG lipids has on the delivery of siRNA to target hepatic genes of interest (Abstract). Mui teaches that LNPs can comprise PEG moieties that have carbon chains of 14, 16, or 18 carbons in length (Abstract). Mui teaches that PEG moieties that have 14 carbon chain lengths were able to successfully deliver siRNA molecules to induce silencing of hepatic genes (pg. 3-5; see Figures 4-5).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the PEG moiety conjugated to an LNP of Rajeev for a PEG moiety that comprises a chain length of 14 carbons and can be conjugated to an LNP, as described by Mui. A person of ordinary skill in the art would have had a reasonable expectation of success because both Rajeev and Mui teach the use of sugar-coated LNPs that can be conjugated to a PEG moiety in order to deliver an siRNA molecule to silence a gene of interest.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rajeev (PG Pub No. US 2021/0299261 A1, published 30 September 2021, filed 4 March 2021) as applied to claims 1-9, 11, and 13-14 above, and further in view of Ding ( "Cross-talk between LOX-1 and PCSK9 in vascular tissues." Cardiovascular research 107.4 (2015): 556-567).
Regarding claim 15, part (iii), Rajeev anticipates claims 1-9, 11, and 13-14 as described above. Rajeev further teaches that the targeting moiety can target cells of the reticular endothelial system (i.e., the LNP can be targeted to an endothelial cell) ([0205]).
Rajeev does not teach or suggest that the second active agent binds to a target group consisting of LOX-1 (Claim 15).
However, one of ordinary skill in the art would have considered the teachings of Ding as both references are common fields of endeavor pertaining to the use of siRNA molecules for the targeting of genes associated with PCSK9 (Abstract).
Ding is directed towards a study concerned with how LOX-1 and PCSK9 interact in vascular tissues (Abstract). Ding teaches the use of siRNA molecules that can target LOX-1 in order to synergistically reduce the expression of both LOX-1 and PCSK9 (pg. 560).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the second active agent of Rajeev for an siRNA molecule that binds to LOX-1, as described by Ding. A person of ordinary skill in the art would have been motivated to do so in order to utilize siRNA molecules that can synergistically reduce the expression of a target PCSK9 gene associated with coronary disease. A person of ordinary skill in the art would have had a reasonable expectation of success because Rajeev teaches that two or more active agents may be utilized and conjugated to a targeting agent in order to reduce the expression of PCSK9 while Ding teaches that siRNA molecules targeting LOX-1 were known in the art to be able to synergistically reduce the expression of PCSK9.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rajeev (PG Pub No. US 2021/0299261 A1, published 30 September 2021, filed 4 March 2021) as applied to claims 1-9, 11, and 13-14 above, and further in view of Zhang ("Lipids and lipid derivatives for RNA delivery." Chemical reviews 121.20 (2021): 12181-12277).
Regarding claim 16, Rajeev anticipates claims 1-9, 11, and 13-14 as described above. Rajeev teaches that the LNP may comprise one or more ionizable lipids selected from Dlin-MC3-DMA (i.e., Rajeev teaches that the LNP may comprise a combination of ionizable lipids) ([0402], [0404]).
Rajeev does not teach or suggest that the LNP further comprises ALC-0315 (Claim 16).
However, one of ordinary skill in the art would have considered the teachings of Zhang as both references are common fields of endeavor pertaining to the use of LNPs for the delivery of nucleic acid molecules of interest to cells.
Zhang is directed towards a review study concerned with lipids and lipid derivatives for RNA delivery (Abstract). Zhang teaches that LNPs comprising GalNAc clusters are targeted to liver hepatocytes (pg. 12247). Zhang teaches that both ALC-0315 was a known ionizable lipid that could be utilized within LNPs and kept shelf stable for as long as three years (pg. 12216-12217). Zhang teaches that LNPs comprising either ALC-0315 or SM-102 were able to be utilized to express an mRNA encoding a reporter luciferase gene (pg. 12214). Zhang teaches that Dlin-MC3-DMA, ALC-0315, and SM-102-base lipid nanoparticles have been approved by the FDA for clinical use in the delivery of nucleic acids of interest (pg. 12252).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute a second ionizable lipid of Rajeev for an ALC-0315 lipid, as described by Zhang. A person of ordinary skill in the art would have had a reasonable expectation of success because Rajeev teaches that two or more ionizable lipids may be present within the LNP while Zhang teaches that ALC-0315 was a known ionizable lipid that could be conjugated to an LNP in order to successfully stabilize the LNP and deliver a nucleic acid of interest to a liver hepatocyte via the use of GalNac clusters.
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.
Claim 1-12 and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-12, 15, and 17-18 of copending Application No. 18/861,189 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims anticipate the instantly pending claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 1, copending claim 15 claims a method for targeting an active agent to a hepatocyte, the method comprising contacting the hepatocyte with a composition comprising an active agent encapsulated by a sugar-conjugated lipid nanoparticle (LNP), optionally a hexose monosaccharide- conjugated LNP, further optionally an N-acetylgalactosamine (GalNAc) conjugated lipid nanoparticle (LNP), wherein the sugar-conjugated LNP comprises a lipid component comprising one or more of D-Lin-MC3-DMA, cholesterol, DSPC, and DMG-2000-PEG, optionally two, three, or four of D-Lin-MC3-DMA, cholesterol, DSPC, and DMG-2000- PEG, further optionally wherein the lipid component comprises cholesterol with one or more GalNAc moieties conjugated thereto, whereby the active agent is targeted to the hepatocyte. Copending claims 17-18 claim that the active agent is an siRNA molecule that targets a PCSK9 gene.
Regarding claim 2, copending claim 15 claims that the sugar is GalNac.
Regarding claim 3, copending claims 1 and 3 claim that the LNP comprises 5-10% cholesterol.
Regarding claim 4, copending claim 15 claims that the LNP comprises a lipid component comprising D-Lin-MC3-DMA.
Regarding claims 5-12, copending claims 5-12 recites identical limitations.
Regarding claim 16, copending claim 15 recites identical limitations.
Claims 13-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim claims 1, 3, 5-12, 15, and 17-18 of copending Application No. 18/861,189 as applied to claims 1-12 and 16 above, further in view of Rajeev (PG Pub No. US 2021/0299261 A1, published 30 September 2021, filed 4 March 2021).
This is a provisional nonstatutory double patenting rejection.
Regarding claims 13-14, copending claims 1, 3, 5-12, 15, and 17-18 anticipate claims 1-12 and 16 as described above.
Copending claims 1, 3, 5-12, 15, and 17-18 do not teach or suggest that the disease is a cardiovascular disease (Claim 13) and the method further comprises administering a second active agent is appropriate for treating the disease, disorder, or condition (Claim 14).
However, one of ordinary skill in the art would have considered the teachings of Rajeev as both references are common fields of endeavor pertaining to the use of LNPs for the delivery of siRNA targeting PCSK9.
The applicable teachings of Rajeev are discussed above as applied to claims 13-14.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the copending method such that the disease was a cardiovascular disease and the method further comprised administering a second active agent, as described by Rajeev. A person of ordinary skill in the art would have been motivated to do so in order to treat cardiovascular diseases through the use of multiple siRNA molecules that target genes associated with coronary disease. A person of ordinary skill in the art would have had a reasonable expectation of success because both the copending claims and Rajeev teach the use of LNPs that can deliver siRNAs of interest to cells of interest in order to silence target genes.
Claim 15 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim claims 1, 3, 5-12, 15, and 17-18 of copending Application No. 18/861,189 in view of Rajeev (PG Pub No. US 2021/0299261 A1, published 30 September 2021, filed 4 March 2021), as applied to claims 13-14 above, further in view of Ding ( "Cross-talk between LOX-1 and PCSK9 in vascular tissues." Cardiovascular research 107.4 (2015): 556-567)
Regarding claim 15, copending claims 1, 3, 5-12, 15, and 17-18 in view of Rajeev render obvious claims 13-14 as described above.
Copending claims 1, 3, 5-12, 15, and 17-18 in view of Rajeev do not teach or suggest that that the second active agent binds to a target group consisting of LOX-1 (Claim 15).
However, one of ordinary skill in the art would have considered the teachings of Ding as both references are common fields of endeavor pertaining to the use of siRNA molecules for the targeting of genes associated with PCSK9 (Abstract).
The applicable teachings of Ding are described above as applied to claim 15.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the second active agent of copending claims 1, 3, 5-12, 15, and 17-18 in view of Rajeev for an siRNA molecule that binds to LOX-1, as described by Ding. A person of ordinary skill in the art would have been motivated to do so in order to utilize siRNA molecules that can synergistically reduce the expression of a target PCSK9 gene associated with coronary disease. A person of ordinary skill in the art would have had a reasonable expectation of success because copending claims 1, 3, 5-12, 15, and 17-18 in view of Rajeev teaches that two or more active agents may be utilized and conjugated to a targeting agent in order to reduce the expression of PCSK9 while Ding teaches that siRNA molecules targeting LOX-1 were known in the art to be able to synergistically reduce the expression of PCSK9.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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/KYLE T REGA/Examiner, Art Unit 1636
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637