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 .
Response to Amendment/Status of Claims
Claims 3,4,14,58,83 and 84 have been amended, claim 5 has been canceled. Claim 118 is new. Claims 3-4,7,13-14,20,58-59,64,66,75-76,78,83-84,95,97,114-115 and 118 are pending and under examination.
Election/Restrictions
Applicant’s election with traverse of the species of the antisense strand of SEQ ID NO: 465 which corresponds to positions 3345-3367, and the sense strand of SEQ ID NO: 165 which corresponds to positions 3347-3367 in Table 2 and which is duplex AD-1290122 in the reply filed on 11/18/2025 is acknowledged. The traversal is on the grounds that the corresponding chemically modified antisense strand sequence for duplex AD-1290122 is SEQ ID NO: 1065 and the corresponding chemically modified sense strand sequence for duplex AD-1290122 is SEQ ID NO: 765 (See Table 3). Applicant submits that the unmodified antisense and sense sequences are identical to the sequences of Duplex AD-1335131 in Table 4 and the nucleotide sequence of the sense strand of AD-1290122 and AD-1335131 are identical and the modification patterns are almost the same, differing only in the modification of the “G” at position 6, and in view of the significant nucleotide sequence and modification overlap, examining these species would not be a significant burden.
This is found persuasive, and therefore the antisense strand of SEQ ID NO: 465 which corresponds to positions 3345-3367, and the sense strand of SEQ ID NO: 165 which corresponds to positions 3347-3367 in Table 2 and which is duplex AD-1290122, as well as the corresponding chemically modified antisense strand sequence for duplex AD-1290122, SEQ ID NO: 1065 and the corresponding chemically modified sense strand sequence for duplex AD-1290122, SEQ ID NO: 765 (See Table 3), as well as the sequences of Duplex AD-1335131 in Table 4 (SEQ ID NOs: 1665 and 1065) will be examined.
Therefore, in light of the amendments, the species election is withdrawn, as the claims are not directed to other species. However, the examiner reserves the right to re-introduce the election if amendments re-introduce species which have been removed from the claims.
The examiner has included the elected sequences from Tables 3 and 4 below for reference. Abbreviations are found on instant page 143.
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Priority
This application is a 371 of PCT/US2021/037437 filed 06/15/2021, which claims benefit of 63/140,532 filed 01/22/2021 and claims benefit of 63/039,897 filed 06/16/2020.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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. See at least page 16, which recites multiple instances of “www.” and “https”.
Claim Objections
Claim 3 is objected to because of the following informalities: lines 2 and 5 recite “ALK”. For clarity, at least the first recitation should recite the full name of the gene. Appropriate correction is required.
Claim 14 is objected to because of the following informalities: part (c) recites “2’-hydroxly-modified nucleotide” and should recite “2’-hydroxyl-modified nucleotide”. Appropriate correction is required. In addition, line 2 of part (f) is missing a space between “GNA” and “modification”.
Claim 20, part (ff) is objected to because of the following informalities: the end of the limitation in part (ff) is missing a semicolon. Appropriate correction is required.
Claim 97 is objected to because of the following informalities: part (j) has a typo at the end (backwards slash) as it recites “triglyceride levels;\”. Appropriate correction is required.
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 7,14,20,66,84,97 and 118 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 7, the claim recites wherein (a); (b); (c); (d); (e); (f); (g); and/or (h). In the case of “and”, it is unclear how all of the limitations of (a); (b); (c); (d); (e); (f); (g); and (h) can be possible and is therefore indefinite.
Regarding claim 14, the claim recites wherein (a); (b); (c); (d); (e); and/or (f). In the case of “and”, it is unclear how all of the limitations of (a); (b); (c); (d); (e); and (f). can be possible and is therefore indefinite. For example, (a) recites “no more than 5 of the sense strand and no more than five of the nucleotides of the antisense strand are unmodified nucleotides” and (b) recites “all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides”. Therefore, it is not possible for both (a) and (b) to be true. In addition claim 14, part (f) recites, “the at least one modified nucleotide is a 2’-O-methyl modification, a GNA modification, and a 2’-fluoro modification. The wording is unclear as to whether these three modifications are meant to be options for the at least one modified nucleotide, in which the claim should recite “or” rather than “and”, or if the claim is intending to require all three of these modifications (2’-O-methyl modification, a GNA modification, and a 2’-fluoro modification) by reciting “and”. If the claim recited Markush language (selected from the group consisting of), then “and” would be proper, however if these are alternatives, then the claim should recite “or”.
Regarding claim 20, the claim recites wherein (a); (b); (c); (d); (e); ….and/or (pp). In the case of “and”, it is unclear how all of the limitations of (a); (b); (c); (d); (e); ….and (pp) can be possible and is therefore indefinite. In addition, claim 20 part (hh), the Markush grouping of “wherein the lipophilic moiety is selected from the group consisting of lipid…or phenoxazine” is improper because by reciting “or” rather than “and” at the end of the list of options, the claim results in an open list of alternatives and is not a closed group of alternatives. See MPEP 2173.05(h).
Regarding claim 66, the claim recites (a); (b); (c); (d); (e); (f); and/or (g). In the case of “and”, it is unclear how all of the limitations of (a); (b); (c); (d); (e); (f); and (g) can be possible and is therefore indefinite.
Regarding claim 84, the claim recites wherein (a); (b); (c); (d); (e); (f);…and/or (k). In the case of “and”, it is unclear how all of the limitations of (a); (b); (c); (d); (e); (f);… and (k) can be possible and is therefore indefinite. For example how can both (f) wherein the subject is overweight and (h) wherein the subject is in need or desire of weight maintenance both be true.
In addition, claim 84, part (i) recites “various types of cancer (e.g., endometrial cancer, esophageal adenocarcinoma, gastric cardia cancer, liver cancer, kidney cancer, pancreatic cancer), mental illness (e.g., depression, anxiety)…”. The phrase “e.g.” and use of parenthesis renders the claim indefinite because it is unclear whether the limitations following the e.g. and what is in parenthesis are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 97, the claim recites wherein (a); (b); (c); (d); (e); (f);…and/or (q). In the case of “and”, it is unclear how all of the limitations of (a); (b); (c); (d); (e); (f);… and (q) can be possible and is therefore indefinite.
Additionally, claim 97, part (d) recites “various types of cancer (e.g., endometrial cancer, esophageal adenocarcinoma, gastric cardia cancer, liver cancer, kidney cancer, pancreatic cancer), mental illness (e.g., depression, anxiety)…”. The phrase “e.g.” and use of parenthesis renders the claim indefinite because it is unclear whether the limitations following the e.g. and what is in parenthesis are part of the claimed invention. See MPEP § 2173.05(d).
Claim 118 recites “the dsRNA agent of claim 3, wherein (a) the sense strand comprises the sequence and all the modifications of SEQ ID NO: 765, and the antisense strand comprises the sequence and all the modifications of SEQ ID NO: 1065”. Page of the instant specification shows the sequence and chemical modification pattern of the recited sequences and the Tables on pages 143-144 describe the abbreviations. The instant specification does not describe or define with “Ghd” means in the sense sequence of SEQ ID NO: 765 below:
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Therefore, claim 118 is indefinite as neither the claim nor the instant specification provides guidance as to what “Ghd” is and therefore the scope of the claim cannot be determined. For purposes of compact prosecution, the examiner is interpreted “Ghd” to mean 2’-O-hexadecyl-guanosine-3’-phosphate.
Claim Rejections-Scope of Enablement
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 83,84,95 and 97 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 an in vitro method of inhibiting expression of an ALK gene in a cell expressing the ALK gene, the method comprising introducing into the cell expressing ALK the dsRNA agent of claim 3, does not reasonably provide enablement for a method of inhibiting expression of an ALK gene in any cell in vitro or any cell in vivo within a subject and does not provide enablement for a method of treating a subject having a disorder that would benefit from reduction in ALK expression or preventing at least one symptom or sign in a subject having a disorder that would benefit from reduction in ALK expression comprising administering to the subject a therapeutically effective amount of the dsRNA of claim 3. 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.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
The Breadth of the Claims and The Nature of the Invention
Claims 83 and 84 encompass the recited method of inhibiting expression of an ALK gene in any cell, whether the cell expresses ALK or not, and encompasses the method occurring in vitro or in vivo, and by any means of introducing the dsRNA agent of claim 3 into the cell. While claim 84, parts (a)-(i) and (k) recite the cell is within a subject, (j) does not recite in a subject and therefore encompasses in vitro. Regarding the breadth of the cells, the claims encompass any type of cells, including plant cells, bacteria, animal cells, mammalian cells, human cells, including cells that do not express ALK.
Claim 95 encompasses treating a subject having any disorder that would benefit from reduction in ALK expression, and therefore encompasses treating a large genus of disorders, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim by any route of administration. Claim 95 also encompasses prevention, including up to 100% prevention of at least one symptom or sign in a subject having any disorder that would benefit from reduction in ALK expression comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim by any route of administration.
Claim 97 encompasses the treatment or prevention of claim 95, and further recites additional ALK-associated disorders, however still encompasses many possible disorders being treated. For example, claim 97 (d) encompasses treating any type of cancer, or any type of breathing problem which encompasses cystic fibrosis, and also the disorders recited may not even be caused by ALK overexpression.
The State of the Prior Art
Regarding the state of the art of RNA interference in vitro vs. in vivo, Lu et al. (Advances in Genetics, 2005 Aug 9, Vol. 54, pgs 115-142) taught the use of siRNA to down-regulate expression of a specific gene has become the method of choice for cell culture or in vitro studies and delivery of the siRNA duplex specifically targeting certain genes of interest in the cell tissue typically has been performed with siRNA targeting an individual gene (page 121, Section B.). Lu et al. taught that down-regulation of individual genes is a powerful tool for understanding the biological function of genes and biochemical pathways in the development and control of pathology, which has led to considerable adoption of siRNA for functional genomics looking for inhibition of genes that can generate therapeutic benefits reversing pathological effects, often caused by overexpression of those same genes, however this approach clearly depends on the effectiveness of siRNA delivery to modulate, very selectively, the expression of specific genes and, as a result, to induce physiological or pharmacological effects. A key requirement is identification of an effective site in the target mRNA sequence for siRNA accessibility. Also, for most applications, effective transfection of the siRNA agent into the cytoplasmic compartment is critical (page 122, first paragraph).
Lu et al. taught the success of in vitro transfection of siRNA into cells for target research has led to a strong interest in extending those studies to in vivo systems. However, in vivo delivery of siRNA into specific tissues of animal disease is much more complicated. Although increasing numbers of studies on target identification and validation using siRNA in vitro have been reported, limited reports of in vivo studies have indicated a lack of effective delivery methods for siRNA agents. The key to in vivo application is a delivery system that transports the siRNA into the target tissue and into the cell cytoplasm, or shRNA expression cassette to the nucleus much like the dependence of gene therapy on appropriate delivery methods (page 122, 2nd paragraph). Lu et al. taught that therapeutic applications depend on optimized local and systemic delivery of siRNA in vivo (page 122, 3rd paragraph).
Regarding in vivo siRNA delivery, Lu et al. taught in vivo siRNA delivery falls into two approaches: local and systemic administration and that for example, skin and muscle can be better accessed using local delivery, whereas lung and tumor can be reached efficiently by both local and systemic deliveries. The choice between local and systemic delivery largely depends on what tissues and cell types are targeted and the expected outcome for siRNA-mediated gene knockdown in terms of biological readout. In addition, the choice usually is only a part of the entire consideration of study design involving vector carriers, administration routes, and approaches for siRNA delivery in vivo (page 126, Section C). Lu et al. taught, to be effective, in vivo functional genomics requires high efficiency in vivo delivery and good activity in a clinically relevant disease model for the clinical indication of interest (page 133, first paragraph) and the development of siRNA as a therapeutic agent faces a number of challenges, especially for systemic routes of administration. The most critical hurdle for in vivo delivery is attaining adequate delivery to disease tissue and cells (page 133, Section B.).
Regarding the state of the art on diseases associated with ALK overexpression,
Holla et al. (Cold Spring Harb Mol Cas Stud. 2017 Jan; 3:a001115) taught the ALK gene plays an important physiologic role in the development of the brain and can be oncogenically altered in several malignancies including non-small-cell lung cancer (NSCLC) and anaplastic large cell lymphomas (ALCL) (Abstract). Holla et al. taught ALK is expressed normally in the brain, small intestine, and testis, but not in the normal lymphoid cells (Introduction, page 1).
Di Paolo et al. (Molecular Therapy, 2011, 19(12):2201-2212) cited on an IDS, taught ALK is involved in the pathogenesis of different types of human cancers, including neuroblastoma (NB), and in neuroblastoma, ALK overexpression or point mutations are associated with poor prognosis and advanced stage disease (Abstract). Di Paolo et al. taught NB patients may have high expression loves of wild-type ALK receptor, and the mechanisms for increased ALK expression are not completely understood (Intro, page 2201). Di Paolo et al. taught that ALK could represent a new therapeutic target specific for the large fraction of NB that overexpress either mutated or amplified WT ALK (page 2202, left column). Di Paolo et al. taught despite considerable potential for RNAi for treating cancer, the major challenge to their wide application is the lack of efficient, selective tumor delivery methods (page 2202, right column).
Di Paolo et al. taught experiments in NB cells transduced with ALK-shRNA, are a strong proof-of-principle that targeting ALK could be an excellent strategy to treat NB tumors. However, transduced cells are an artificial model and we sought to obtain a therapeutic tool potentially applicable to untransduced NB cells. To this end, we used coated cationic liposomes (CCL) to entrap ALK-specific siRNA; CCL were previously showed to be efficient in condensing and carrying nucleic acids or antisense oligodeoxynucleotides, and in increasing their delivery and therapeutic effect in vivo. To increase the selective delivery of ALK-specific siRNA to NB cells, CCL was surface-grafted with anti-GD2 antibodies, since GD2 is expressed by NB cells at higher levels than other tissues. targeted liposomes entrapping siRNA, after coupling of whole anti-GD2 antibodies is abbreviated TL[siRNA] (page 2204, left column). Di Paolo et al. taught intra-mass injection of ALK-siRNA and TL[ALK-siRNA] in mice with NB, and showed potent knockdown of ALK protein by TL[ALK-siRNA], and strong induction of apoptosis compared to other treatments (page 2205, left column).
Therefore, Di Paolo et al. taught ALK knockdown in vivo using TL[ALK-siRNA] which are coated cationic liposomes entrapping the ALK-siRNA, and which is grafted with anti-GD2 antibodies to target to NB cells, by local administration to the tumor.
Majumder et al. (Biochemical Journal, 14 Sept 2021, 478, 3297-3317) taught both ALK and RTK (receptor tyrosine kinase) exhibit significant and consistent functional down-regulation in post-mortem Alzheimer’s disease and Type 2 Diabetes tissues (Abstract). Therefore, if ALK is down-regulated in Type 2 Diabetes tissue, it would be unpredictable that inhibiting the expression of ALK would result in treating Type 2 Diabetes.
The Level of Predictability in the Art
The instant claimed invention is highly unpredictable due to claims 83 and 84 encompassing inhibiting expression of an ALK gene in any cell in vitro or in vivo, comprising introducing into the cell the dsRNA agent of claim 3. It is unpredictable that if the cell does not express ALK, that the recited method would result in inhibiting expression of an ALK gene. For example, it is unpredictable that the recited method would be carried out in a plant cell, as there is no evidence that plants express ALK. As shown above by Holla et al., the ALK gene can be oncogenically altered in several malignancies including non-small-cell lung cancer (NSCLC) and anaplastic large cell lymphomas (ALCL) (Abstract), and is expressed normally in the brain, small intestine, and testis, but not in the normal lymphoid cells (Introduction, page 1). Therefore, not all cells and tissues express ALK.
In addition, regarding the unpredictability of extrapolating in vitro results to in vivo, Lu et al. taught that therapeutic applications depend on optimized local and systemic delivery of siRNA in vivo and to be effective, in vivo functional genomics requires high efficiency in vivo delivery and good activity in a clinically relevant disease model for the clinical indication of interest and the development of siRNA as a therapeutic agent faces a number of challenges, especially for systemic routes of administration, and the most critical hurdle for in vivo delivery is attaining adequate delivery to disease tissue and cells. It is noted that none of claims 83,84,95 or 97 recite using any specific delivery means for the dsRNA, any specific administration route, or using chemically modified dsRNA in order to effectively delivery the dsRNA to the target tissue or cells. The claims recite using the dsRNA of claim 3 which just recites that the antisense strand comprises a region of complementarity of at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the antisense nucleotide sequence set forth in SEQ ID NO: 465. The dsRNA in these claims is not conjugated to a lipophilic moiety and are not chemically modified to enhance stabilization or delivery to target tissues.
It is unpredictable, that the recited method is capable of treating all of the recited diseases encompassed by an ALK-associated disorder as in claims 95 and 97. As shown by Majumder et al., ALK is down-regulated in post-mortem Type 2 Diabetes tissues (Abstract). Therefore, it would be unpredictable that further inhibition of ALK expression would result in treating Type 2 Diabetes. In addition, claim 97 encompasses various types of cancer, including solid tissue cancers as well as blood cancers. The state of the art shows the association of ALK overexpression with certain types of cancer (non-small-cell lung cancer (NSCLC) and anaplastic large cell lymphomas per Holla et al. and neuroblastoma (NB) per Di Paolo et al., but not all types of cancer are associated with ALK overexpression and therefore it is unpredictable that any type of cancer is capable of being treated by the recited method.
It is unpredictable to be able to prevent a symptom or sign in a subject having a disorder that would benefit from reduction in ALK expression as in claims 95 and 97 if one does not yet have the disorder.
The Amount of Direction Provided by the Inventor and
The Presence or Absence of Working Examples
Regarding claims 83,84,95 and 97, the specification does not enable any person skilled in the art to which it pertains to make and/or use the invention commensurate in scope with the claims. The instant specification discloses single dose reporter screen for human ALK siRNAs in Hepa1-6, mouse hepatoma cells which were transfected with 5 uL of 1 ng/uL of each siRNA duplex to an individual well in a 96-well plate, and that a single dose experiment was performed at 10nM final duplex concentration, the results of which are shown in Table 5 and presented as the average percent ALK mRNA remaining compared to a negative control (Example 3, page 142). Table 5 starts on page 178 and goes through page 186. Therefore, the working examples show an in vitro method of inhibiting expression of an ALK gene in a cell expressing ALK. However, there are no working examples showing the recited methods in any cells that do not express ALK, and there are no in vivo examples showing inhibiting the expression of an ALK gene in a cell within a subject, and there are no examples showing any treatment of a subject having a disorder that would benefit from reduction in ALK expression or prevention of at least one symptom or sign in a subject having a disorder that would benefit from reduction in ALK expression.
Lu et al. cited above shows the problems and challenges of in vivo siRNA delivery compared to in vitro use and that in vivo delivery of siRNA into specific tissues of animal disease is much more complicated, and that therapeutic applications depend on optimized local and systemic delivery of siRNA in vivo. Therefore, the instant specification and examples do not show how to carry out the recited methods of claims 83,84,95 and 97 in vivo in a subject regarding the administration route for particular diseases, or the delivery vehicle in order to target the specific cells expressing ALK. Lu et al. taught, to be effective, in vivo functional genomics requires high efficiency in vivo delivery and good activity in a clinically relevant disease model for the clinical indication of interest (page 133, first paragraph) and the most critical hurdle for in vivo delivery is attaining adequate delivery to disease tissue and cells (page 133, Section B.).
The Quantity of Experimentation Necessary
Regarding claims 83,84,95 and 97, in light of the unpredictability surrounding the breadth of the claimed method, one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. As the examples only show in vitro examples of reduction of ALK expression in Hepa1-6 mouse hepatoma cells, further experimentation would be needed to determine if the in vitro method would be capable of being carried out in other cells, including those that do not express ALK, such as plant cells, or other animal cells that do not normally express ALK. Further experimentation would be needed for the in vivo methods where the recited methods are occurring in a cell in a subject, or for treating a subject having a disorder that would benefit from reduction in ALK expression, or preventing a symptom or sign in a subject having a disorder that would benefit from reduction in ALK expression, as many diseases are encompassed by these methods which would require undue experimentation in many disease-relevant animal models, experimentation regarding the route of administration for particular diseases, and further experimentation regarding delivery means for the dsRNA agent to reach the particular cells/tissues to achieve the recited effects.
Therefore, given the lack of guidance present in the specification for the recited method (a method of inhibiting expression of an ALK gene in a cell, the method comprising introducing into the cell the dsRNA agent of claim 3; a method of treating a subject having a disorder that would benefit from reduction in ALK expression, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 3; or preventing at least one symptom or sign in a subject having a disorder that would benefit from reduction in ALK expression, comprising administering to the subject a prophylactically effective amount of the dsRNA agent of claim 3), further experimentation would be required and would be considered undue.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
After applying the Wands factors and analysis to claims 83,84,95 and 97, in view of the applicant’s entire disclosure, it is concluded that the specification is not enabled for the full scope as discussed above. Therefore, claims 83,84,95 and 97 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the invention commensurate in scope with these claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 3 and 4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by McSwiggen et al. (WO 03070193, Published 28 August 2003).
Claim Interpretation: Regarding claims 3 and 4, the preamble recites an intended use (“for inhibiting expression of ALK”). As the body of the claim sets forth all of the limitations of the claimed invention, the intended use in the preamble is not being considered a claim limitation. See MPEP2111.02: If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020)
Regarding claims 3 and 4(b), McSwiggen et al. teach compounds and compositions for modulating the expression and activity of HIV genes using short interfering nucleic acid (siNA), short interfering RNA (siRNA) and double-stranded RNA (Page 6, lines 18-27). McSwiggen et al. teach double-stranded short interfering nucleic acid molecules wherein one of the strands is an antisense strand and the other strand is a sense strand (page 7, lines 12-17). McSwiggen et al. teach the antisense region of the siRNA can comprise a sequence having any of SEQ ID NOs 739-1476 (page 16, lines 14-15). McSwiggen et al. teach the following double-stranded RNA in Table II on page 134, in which the siNA lower sequence (antisense) is SEQ ID NO: 962.
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As shown in the alignment below, the antisense strand of SEQ ID NO: 962 of McSwiggen et al. (Db) comprises 17 contiguous nucleotides differing by 2 nucleotides from the instant antisense sequence of SEQ ID NO: 465 (Qy):
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Additionally, shown below is the alignment of the antisense sequence SEQ ID NO: 962 of McSwiggen et al. (Qy) with the mRNA sequence of GenBank Accession No. NM_004304.4 (Homo sapiens ALK) (Db) showing the complementarity of SEQ ID NO: 962 to mRNA encoding ALK:
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Claim Rejections - 35 USC § 102/103
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.
Claims 13,14,20,66,75,76,78,83,114 and 115 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over McSwiggen et al. as applied to claims 3 and 4 above.
The teachings of McSwiggen et al. as applicable to claims 3 and 4 have been described above in the 35 U.S.C. 102(a)(1) rejection.
Regarding claims 13 and 14(c),(d) and (f), McSwiggen et al. teach the invention features various chemically-modified synthetic short interfering nucleic acid molecules, which improves various properties through increased resistance to nuclease degradation in vivo and/or improved cellular uptake (page 7, lines 2-7). McSwiggen et al. teach various chemical modifications, including any pyrimidine nucleotide (one or more or all) in the sense strand are 2’-deoxy-2’-fluoro pyrimidine nucleotides and any purine nucleotides (one or more or all) in the sense strand are 2’-deoxy purine nucleotides, or the antisense strand comprises one or more 2’-deoxy-2’-fluoro pyrimidine nucleotides and any purine nucleotides are 2’-O-methyl purine nucleotides (page 8, lines 6-9,13-17).
Regarding claim 20(a) and (b), McSwiggen et al. teach the antisense strand of the siRNA molecule comprises a phosphorothioate internucleotide linkage at the 3’- end of the antisense strand (page 8, lines 18-20, page 20, lines 4-5), and the antisense region can comprise about one to about five phosphorothioate internucleotide linkages at the 5’ end of the antisense region (page 20, lines 5-7).
Regarding claim 20(c),(l),(m) and (n), McSwiggen et al. teach each strand of the siRNA molecule comprises 21 nucleotides (page 8, line 30). McSwiggen et al. teach each strand has about 19 to about 29 nucleotides (page 17, lines 8-11).
Regarding claim 20(d) and (e), McSwiggen et al. teach duplexes with overhanging ends of about 1 to about 3 nucleotides for example about 21 nucleotide duplexes with about 19 base pairs and 3’-terminal mononucleotide, dinucleotide or trinucleotide overhangs (page 18, lines 19-23).
Regarding claim 66(f), McSwiggen et al. teach the 5’-end of the antisense strand includes a phosphate group (page 8, lines 21-22).
Regarding claim 75, McSwiggen et al. teach a mammalian cell which can be a human cell comprising an expression vector comprising a nucleic acid sequence encoding at least one siRNA molecule of the invention in a manner that allows expression of the nucleic acid molecule (page 20, lines 12-16; page 64 lines 20-22).
Regarding claim 76, McSwiggen et al. teach a pharmaceutical composition comprising a siNA molecule of the invention in an acceptable carrier or diluent (page 10 lines 13-14).
Regarding claim 78, McSwiggen et al. teach a pharmaceutical composition comprising one or more nucleic acids of the invention in an acceptable carrier, such as a stabilizer, buffer and the like (page 89, lines 29-31). McSwiggen et al. teach pharmaceutical compositions can be in the form of sterile injectable aqueous suspension, and acceptable vehicles and solvents are water (page 95, lines 1,2,7).
Regarding claim 83, McSwiggen et al. teach methods of modulating the expression of a HIV gene within a cell comprising introducing the siRNA molecule into a cell under conditions suitable to modulate the expression of the HIV gene in the cell (pages 42-45). McSwiggen et al. teach the siNA molecules of the invention can be designed to inhibit target gene expression (page 47, lines 9-10). Although McSwiggen et al. is silent about inhibiting expression of an ALK gene in the cell it does not appear that the claim language or limitations result in a manipulative difference in the method steps when compared to the prior art disclosure. See Bristol-Myers Squibb Company v. Ben Venue Laboratories, 58 USPQ2d 1508 (CAFC 2001). “It is a general rule that merely discovering and claiming a new benefit of an old process cannot render the process again patentable.” In re Woodruff, 16 USPQ2d 1934, 1936 (Fed. Cir. 1990). Granting a patent on the discovery of an unknown but inherent function would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art. In re Baxter Travenol Labs, 21 USPQ2d 1281 (Fed. Cir. 1991). See M.P.E.P. 2145. The fact that Applicant may have discovered yet another beneficial effect from the method set forth in the prior art does not mean that they are entitled to receive a patent on that method. Thus, McSwiggen et al. teaches, either expressly or inherently implied, each and every limitation of claim 83.
Regarding claim 114, McSwiggen et al. teach a kit containing a siRNA molecule of the invention, which can be chemically modified, and that can be used to modulate the expression of a HIV target gene in a cell, tissue or organism (page 51, lines 19-21), and that the kit including a siNA molecule of the invention and a vehicle that promotes introduction of the siRNA into cells of interest, and that the kit can be used for target validation, such as in determining gene function and/or activity, or in drug optimization, drug discovery (page 58, lines 11-18).
Regarding claim 115, McSwiggen et al. teach administration of siRNA molecules of the invention, and delivery of nucleic acid molecules can be delivered by direct injection or by use of an infusion pump, and that direct injection of the nucleic acid molecules of the invention can take place using standard needle and syringe methodologies (page 89). Therefore, McSwiggen et al. teach a syringe comprising the dsRNA.
Therefore, claims 13,14,20,66,75,78,83,114 and 115 are anticipated by McSwiggen et al.
In the alternative, McSwiggen et al. does not explicitly teach that the double stranded siNA comprising the antisense sequence of SEQ ID NO: 962 has the limitations as recited in claims 13,14,20,66,75,78,83,114 and 115.
However, McSwiggen et al. teaches “the siNA of the invention” or “the invention features one or more siNA molecules” that can comprise the limitations as described above, and teaches the above benefits of the limitations.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, that the double stranded siNA of McSwiggen et al. comprising the antisense sequence of SEQ ID NO: 962 would comprises at least one modified nucleotide, including 2’-O-methyl nucleotides, 2’-deoxy-2’-fluoro nucleotides, or 2’-deoxy nucleotides, at least one phosphorothioate internucleotide linkage, one to about five phosphorothioate internucleotide linkages at the 5’ end of the antisense region or a 5’ phosphate, and for each strand of the siRNA molecule to comprise 21 nucleotides or about 19 to about 29 nucleotides with a reasonable expectation of success. There would be a reasonable expectation of success, because this would amount to applying a known technique of chemical modification to a known product (siNA) ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to provide the double stranded siNA of McSwiggen et al. with such modifications, because McSwiggen et al. teach the invention features various chemically-modified synthetic short interfering nucleic acid molecules, which improves various properties through increased resistance to nuclease degradation in vivo and/or improved cellular uptake (page 7, lines 2-7).
Accordingly, the limitations of claims 13,14,20 and 66 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, for a cell to contain the double stranded siNA comprising the antisense sequence of SEQ ID NO: 962 of McSwiggen et al. with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to provide a cell with the double stranded siNA comprising the antisense sequence of SEQ ID NO: 962 in order to express the siNA and modulate expression of a target gene within the cell.
Accordingly, the limitations of claim 75 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to provide a pharmaceutical composition comprising the double stranded siNA comprising the antisense sequence of SEQ ID NO: 962 of McSwiggen et al., and a buffer or water with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so in order to provide a composition to be administered to a subject for treatment as McSwiggen et al. teach a pharmaceutical composition comprising a siNA molecule of the invention in an acceptable carrier or diluent (page 10 lines 13-14) and teach a pharmaceutical composition comprising one or more nucleic acids of the invention in an acceptable carrier, such as a stabilizer, buffer and the like (page 89, lines 29-31) and pharmaceutical compositions can be in the form of sterile injectable aqueous suspension, and acceptable vehicles and solvents are water (page 95, lines 1,2,7).
Accordingly, the limitations of claims 76 and 78 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to introduce the double stranded siNA comprising the antisense sequence of SEQ ID NO: 962 of McSwiggen et al. into a cell with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so because McSwiggen et al. taught methods of modulating the expression of a HIV gene within a cell comprising introducing the siRNA molecule into a cell under conditions suitable to modulate the expression of the HIV gene in the cell (pages 42-45) and the siNA molecules of the invention can be designed to inhibit target gene expression (page 45, page 47, lines 9-10). Although McSwiggen et al. is silent about inhibiting expression of an ALK gene in the cell it does not appear that the claim language or limitations result in a manipulative difference in the method steps when compared to the prior art disclosure. See Bristol-Myers Squibb Company v. Ben Venue Laboratories, 58 USPQ2d 1508 (CAFC 2001). “It is a general rule that merely discovering and claiming a new benefit of an old process cannot render the process again patentable.” In re Woodruff, 16 USPQ2d 1934, 1936 (Fed. Cir. 1990). Granting a patent on the discovery of an unknown but inherent function would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art. In re Baxter Travenol Labs, 21 USPQ2d 1281 (Fed. Cir. 1991). See M.P.E.P. 2145. The fact that Applicant may have discovered yet another beneficial effect from the method set forth in the prior art does not mean that they are entitled to receive a patent on that method. Thus, McSwiggen et al. teaches, either expressly or inherently implied, each and every limitation of claim 83.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to provide a kit or a syringe comprising the double stranded siNA comprising the antisense sequence of SEQ ID NO: 962 of McSwiggen et al. with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to provide a kit comprising a siRNA molecule of the invention as taught by McSwiggen et al., that can be used to modulate the expression of a HIV target gene in a cell, tissue or organism (page 51, lines 19-21), and that the kit including a siNA molecule of the invention and a vehicle that promotes introduction of the siRNA into cells of interest, and that the kit can be used for target validation, such as in determining gene function and/or activity, or in drug optimization, drug discovery (page 58, lines 11-18). One of ordinary skill in the art would have been motivated to provide a syringe comprising the double stranded siNA because McSwiggen et al. taught administration methods of the siNA molecules of the invention include direct injection of the nucleic acid molecules of the invention using standard needle and syringe methodologies (page 89)
Accordingly, the limitations of claims 114 and 115 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 7,58,59 and 64 are rejected under 35 U.S.C. 103 as being unpatentable over McSwiggen et al. as applied to claims 3 and 4, above, and further in view of Bettencourt et al. (US 20160115476, Published 28 April 2016).
The teachings of McSwiggen et al. as applicable to claims 3 and 4 are described above.
McSwiggen et al. teaches a siNA may comprise a conjugate covalently attached to the chemically modified siNA molecule, the conjugate can be covalently attached to the chemically modified siNA molecule via a biodegradable linker, and the conjugate molecule is attached at the 3’ end of either the sense or antisense strand or both strands, or the conjugate molecule is attached at the 5’ end of either the sense or antisense strand or both strands, and the conjugate molecule may be a ligand for a cellular receptor that can mediate cellular uptake (page 37).
McSwiggen et al. do not teach wherein the sense strand, the antisense strand or both the sense and the antisense strand is conjugated to one or more lipophilic moieties, or that the lipophilic moieties are conjugated to one or more internal positions on at least one strand in the double stranded region of the dsRNA.
Before the effective filing date, Bettencourt et al. taught iRNA agents and that they can be in the form of conjugates and may be attached at any suitable location in the iRNA molecule, e.g. at the 3’ end or the 5’ end of the sense or antisense strand (paragraph 0348). Bettencourt et al. taught that the iRNA agent is chemically linked to one or more conjugates, which may confer functionality by enhancing the activity, cellular distribution or cellular uptake of the iRNA, and that such moieties include lipid moieties such as a cholesterol moiety, cholic acid, a thiocholesterol, a phospholipid (paragraph 0349). Bettencourt et al. taught lipid conjugates can increase resistance to degradation of the conjugate, increase targeting or transport into the target cell or cell membrane and/or be used to adjust binding to a serum protein (paragraph 0364) or can be used to modulate the binding of the conjugate to a target tissue (paragraph 0365). Bettencourt et al. taught that 3’ ligand conjugated strands can be synthesized using a solid support containing the corresponding ligand, and for example the introduction of cholesterol unit in the sequence is performed from a hydroxyprolinol-cholesterol phosphoramidite (paragraph 0668). Bettencourt et al. taught conjugation of ligands to the 5’ end and/or internal positions is achieved by using appropriately protected ligand-phosphoramidite building block (paragraph 0688). Therefore, Bettencourt et al. taught the lipophilic moiety is conjugated via a carrier which is hydroxyprolinol (a pyrrolidinyl), and can be conjugated to the internal positions.
Bettencourt et al. taught iRNA agents in the form of conjugates, e.g. a carbohydrate conjugate which may serve as a targeting moiety and/or ligand, attached to the 3’ end of the sense strand of the dsRNA, and the conjugate make be attached by a linker (paragraph 0027). Bettencourt et al. taught the conjugate comprises one or more acetylgalactosamine (GalNAc) derivatives, which targets the RNAi agents to a particular cell (paragraph 0028).
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the sense strand, antisense strand or both strands of the siNA of McSwiggen et al. to form a conjugate with one or more lipophilic moieties, or conjugation of the lipophilic moieties to internal positions of the ds siNA with a reasonable expectation of success. There would be a reasonable expectation of success, because McSwiggen et al. suggests the siNA may comprise a conjugate covalently attached to the chemically modified siNA molecule, the conjugate can be covalently attached to the chemically modified siNA molecule via a biodegradable linker, and the conjugate molecule is attached at the 3’ end of either the sense or antisense strand or both strands, or the conjugate molecule is attached at the 5’ end of either the sense or antisense strand or both strands, and the conjugate molecule may be a ligand for a cellular receptor that can mediate cellular uptake, and both McSwiggen et al. and Bettencourt pertain to dsRNA for inhibiting gene expression of a target gene and therefore are in the same field of endeavor. One of ordinary skill in the art would have been motivated to modify the sense strand or antisense strand or both of the ds siNA of McSwiggen et al. by conjugating to one or more lipophilic moieties, or for one or more lipophilic moieties to be conjugated to one or more internal positions on at least one strand in the ds region of the ds siNA, because Bettencourt et al. taught iRNA agents can be in the form of conjugates and may be attached at any suitable location in the iRNA molecule, e.g. at the 3’ end or the 5’ end of the sense or antisense strand (paragraph 0348) and that conjugation of ligands to the 5’ end and/or internal positions is achieved by using appropriately protected ligand-phosphoramidite building block (paragraph 0688), and for example the introduction of cholesterol unit in the sequence is performed from a hydroxyprolinol-cholesterol phosphoramidite (paragraph 0668), and teach the benefits of such a lipophilic conjugation which include enhancing the activity, cellular distribution or cellular uptake of the iRNA and that lipid conjugates can increase resistance to degradation of the conjugate, increase targeting or transport into the target cell or cell membrane and/or be used to adjust binding to a serum protein (paragraph 0364) or can be used to modulate the binding of the conjugate to a target tissue (paragraph 0365).
Accordingly, the limitations of claims 7,58 and 59 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the siNA of McSwiggen et al. to comprise a targeting ligand which is a GalNAc conjugate with a reasonable expectation of success. There would be a reasonable expectation of success, because McSwiggen et al. suggests the siNA may comprise a conjugate covalently attached to the chemically modified siNA molecule, and the conjugate molecule may be a ligand for a cellular receptor that can mediate cellular uptake. One of ordinary skill in the art would have been motivated to provide the siNA of McSwiggen et al. with a targeting ligand which is a GalNAc conjugate because Bettencourt et al. taught iRNA agents in the form of conjugates, e.g. a carbohydrate conjugate which may serve as a targeting moiety and/or ligand, attached to the 3’ end of the sense strand of the dsRNA, and the conjugate make be attached by a linker (paragraph 0027) and taught the conjugate comprises one or more acetylgalactosamine (GalNAc) derivatives, which targets the RNAi agents to a particular cell (paragraph 0028).
Accordingly, the limitations of claim 64 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 3 and 118 are rejected under 35 U.S.C. 103 as being unpatentable over Haack et al. (US 20120101108, Published 26 April 2012) in view of NCBI Reference Sequence Accession number NM_004304 (publicly available 07 May 1999), Bettencourt et al. (US 20160115476, Published 28 April 2016), and Maier et al. (US 20170275626, Published 28 Sept 2017).
Claim Interpretation: The examiner has included the elected sequences from Tables 3 and 4 below for reference. Abbreviations are found on instant pages 143-144. It is noted that the instant specification does not define what ‘Ghd’ abbreviation stands for in Table 1 or elsewhere in the specification. The examiner is interpretating ‘Ghd’ to mean 2’-O-hexadecyl-guanosine-3’-phosphate.
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The above chemical modification motif can be summarized as below:
Sense strand SEQ ID NO: 765: positions 1-5,8,12-21 2’-OMe; positions 7,9-11 2’-F, position 6 Ghd (2’-O-hexadecyl-guanosine-3’-phosphate).
Antisense strand SEQ ID NO: 1065: 5’ vinyl-phosphonate, positions 1,3-5,7,10-13,15,17-23 2’-OMe; positions 2,6,8,9,14,16 2’-F.
Sense strand SEQ ID NO: 1665: positions 1-6,8,12-21 2’-OMe; positions 7,9-11 2’-F.
Regarding claims 3 and 118, Haack et al. teach the association of ALK as driving proliferation and survival of the subset of kidney cancer in which it is expressed and is not known to be expressed in normal kidney tissue and cells (paragraph 0043), and that a patient whose kidney cancer expresses a polypeptide with ALK activity may respond favorably to administration of an ALK inhibitor (paragraph 0044). Haack et al. teach siRNA compositions which inhibit the activity of ALK through the process of RNA interference may be employed in the methods of the invention, and that RNA interference and the selective silencing of target protein expression by introduction of exogenous small double-stranded RNA molecules comprising sequence complementary to mRNA encoding the target protein has been well described in the art (paragraph 0175). Haack et al. teach that detailed technical manuals on the design, construction, and use of dsRNA for RNAi are available, See e.g., Dharmacon’s “RNAi Technical Reference and Application Guide”; Promega’s “RNAi: A Guide to Gene Silencing”, that that ALK-inhibiting siRNA products are also commercially available and may be employed in the methods of the invention (paragraph 0177). Haack et al. teach that small dsRNA less than 49 nt in length, preferable 19-25 nucleotides comprising at least one sequence that is substantially identical to part of a target mRNA sequence are most effective in mediating RNAi in mammals (paragraph 0178). Haack et al. teach if the sequence of the gene to be targeted in a mammal is known, 21-23 nt RNAs can be produced and tested for their ability to mediate RNAi in a mammalian cell such as a human or other primate cell, and then can be tested in an appropriate animal model to further assess their in vivo effectiveness (paragraph 0179). Haack et al. also teach the sequences of effective dsRNA can be rationally designed/predicated screening the target mRNA of interest for target sites using a computer folding algorithm, and various parameters may be used to determine which sites are the most suitable target sites within the target RNA sequence (paragraphs 0180,0181).
Haack et al. do not teach the sense strand comprises the sequence and all the modifications of SEQ ID NO: 765, and the antisense strand comprises the sequence and all the modification of SEQ ID NO: 1065.
A blast search of the sense sequence of instant SEQ ID NO: 765 shows that nucleotides 1-20 of SEQ ID NO: 765 aligns with nucleotides 3322-3341 of Homo sapiens ALK receptor tyrosine kinase (ALK) transcript variant 1, mRNA of NM_004304.5.
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Likewise, a blast search of the antisense sequence of instant SEQ ID NO: 1065 shows nucleotides 2-23 of SEQ ID NO: 1065 aligns with nucleotides 3341-3320 of Homo sapiens ALK receptor tyrosine kinase (ALK) transcript variant 1, mRNA of NM_004304.5.
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The mRNA sequence of Homo sapiens ALK transcript variant 1 of NCBI Reference sequence NM_004304 was publicly available before the effective filing date (07 May 1999) and the mRNA sequence is shown below.
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Before the effective filing date, Bettencourt taught iRNA agents chemically linked to one or more ligands, moieties or conjugates which may confer functionality, by enhancing the activity, cellular distribution, or cellular uptake of the RNAi, and such moieties include a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate (paragraph 0349) and taught that oligonucleotides can contain the nucleotide (Chd) or “2-O-hexadecyl-cytidine-3’-phosphate” (Table 1, page 67).
Maier et al. taught dsRNA agents comprising a sense strand and antisense strand with various motifs, the sense strand having a length of 21 nucleotides, 2’-OMe modifications at positions 1-6,8,10,12-21, 2’F modifications at position 7 and 9, and phosphorothioate internucleotide linkages between nt positions 1 and 2 and 2 and 3, and taught the antisense strand having a length of 23 nucleotides, 2’-OMe modifications at positions 1,3,7,9,11,13,15,17,19-23 and 2’-F modifications at positions 2,4-6,8,10,12,14,16 and 18; phosphorothioate internucleotide linkages between positions 1 and 2 and 2 and 3, and between positions 21 and 22 and 22 and 23 counting from the 5’ end (paragraphs 0150-0158). Maier et al. also taught dsRNA agents comprising a sense strand comprising 2’-F modifications at positions 10 and 11 (paragraph 0171) and a sense strand comprising 2’-F modifications at positions 9-11 and 2’-OMe modifications at positions 1-6,8 and 12-21 (paragraph 0198) and phosphorothioate internucleotide linkages between nt positions 1 and 2 and 2 and 3, and an antisense strand comprising 2’-F modifications at positions 2,6,9,14 and 16, and 2’-OMe modifications at positions 1,3-5,7,8,10-13,15 and 17-23 (paragraph 0202) and phosphorothioate internucleotide linkages between positions 1 and 2 and 2 and 3, and between positions 21 and 22 and 22 and 23 counting from the 5’ end (paragraph 0203).
Maier et al. taught dsRNA agents with a 5’-VP on the antisense strand (paragraphs 0052,0056), and the presence of a 5’-VP generally improves the in vivo activity (Paragraph 0247, Fig. 17).
Maier et al. taught the inventors found that having 2’-OMe modifications at nucleotide positions 2 and 14 from the 5’ end of the antisense strand dampened gene silencing activity (paragraph 0261).
Therefore, it was known in the prior art to provide a dsRNA wherein the sense strand has heavy 2'-O-methyl modifications in the 5' and 3' regions and 2’-F in positions 7 and 9-11, and incorporate a 2'-O-hexadecyl nucleoside (e.g., guanosine). Similarly, it was known in the art to formulate the antisense strand having a 5' VP and a mixture of 2'-O-methyl and 2'-F with at least 7 consecutive 2'-O-methyl in the 3' region of the antisense, as well as the phosphorothioate internucleotide linkages at the recited positions in the sense and antisense sequences.
Although the cited art does not specifically teach the exact modification pattern, it would have been obvious for one ordinarily skilled in the art to perform routine optimization of the pattern to achieve improved results. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05 provides In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."
In the instant case, the focus is in the change of form, or substitution of equivalents over the prior art. Substitution of equivalents in terms of identifying optimal locations, both in terms of potency and reduced toxic effects, for 2’F and 2’-OMe modifications in dsRNA, since varying 2’-F and 2’-OMe positions in a double stranded nucleic acid for optimal or better results in known in the prior art.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to provide a dsRNA agent that inhibits ALK expression as taught by Haack et al. to treat kidney cancer, and use the teachings of Haack et al. regarding if the sequence of the gene to be targeted in a mammal is known that 21-23 nt RNAs can be produced and tested for their ability to mediate RNAi and that sequences of effective dsRNA can be rationally designed/predicated screening the target mRNA of interest for target sites using a computer folding algorithm, in view of NCBI Reference Sequence Accession number NM_004304, and the teachings of Bettencourt et al. and Maier et al., and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to design and provide a dsRNA agent that targets ALK and to use the known mRNA sequence of NCBI Reference Sequence Accession number NM_004304 to arrive at the instant sequences of SEQ ID NOs: 765 and 1065 or SEQ ID NOs: 1665 and 1065 based on the teachings of Haack et al., which taught the association of ALK as driving proliferation and survival of the subset of kidney cancer in which it is expressed (paragraph 0043), and that a patient whose kidney cancer expresses a polypeptide with ALK activity may respond favorably to administration of an ALK inhibitor (paragraph 0044), and that siRNA compositions which inhibit the activity of ALK through the process of RNA interference may be employed in the methods of the invention. In addition, because the mRNA sequence of ALK (NCBI Reference Sequence Accession number NM_004304) was publicly available, and nucleotides 1-20 of SEQ ID NO: 765 aligns with nucleotides 3322-3341 of Homo sapiens ALK receptor tyrosine kinase (ALK) transcript variant 1, mRNA of NM_004304.5, and instant nucleotides 2-23 of SEQ ID NO: 1065 aligns with nucleotides 3341-3320 of Homo sapiens ALK receptor tyrosine kinase (ALK) transcript variant 1, mRNA of NM_004304.5, an ordinary artisan could have used the teachings of Haack et al. to arrive at the instant sense and antisense sequences with a reasonable expectation of success, because Haack et al. taught that detailed technical manuals on the design, construction, and use of dsRNA for RNAi are available, See e.g., Dharmacon’s “RNAi Technical Reference and Application Guide”; Promega’s “RNAi: A Guide to Gene Silencing”, that that ALK-inhibiting siRNA products are also commercially available and may be employed in the methods of the invention (paragraph 0177), that that small dsRNA less than 49 nt in length, preferably 19-25 nucleotides comprising at least one sequence that is substantially identical to part of a target mRNA sequence are most effective in mediating RNAi in mammals (paragraph 0178), and that if the sequence of the gene to be targeted in a mammal is known, 21-23 nt RNAs can be produced and tested for their ability to mediate RNAi in a mammalian cell such as a human or other primate cell or the sequences of effective dsRNA can be rationally designed/predicated screening the target mRNA of interest for target sites using a computer folding algorithm, and various parameters may be used to determine which sites are the most suitable target sites within the target RNA sequence (paragraphs 0180,0181).
One of ordinary skill in the art would have been motivated to arrive at the specific modification pattern based on the combined teachings of Bettencourt et al. that iRNA agents chemically linked to one or more ligands, moieties or conjugates which may confer functionality, by enhancing the activity, cellular distribution, or cellular uptake of the RNAi, and such moieties include a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate (paragraph 0349) and taught that oligonucleotides can contain the nucleotide (Chd) or “2-O-hexadecyl-cytidine-3’-phosphate” (Table 1, page 67), and therefore would be motivated to provide a 2’-O-hexadecyl modification on other nucleotides including guanosine with a reasonable expectation of success, and Maier et al. teaching the phosphorothioate, 2’-O-Me, 2’-F at specific positions, and a 5’-VP on the antisense strand which improves the in vivo activity and that having 2’-OMe modifications at nucleotide positions 2 and 14 from the 5’ end of the antisense strand dampened gene silencing activity (paragraph 0261).
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Claims 3-4,7,13-14,20,58-59,64,66,75-76,78,83-84,95,97,114-115 and 118 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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/STEPHANIE L SULLIVAN/ Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636