DETAILED ACTION
Claims 4-10, 13-14, 16-17, 20-21, 23-25, 28, 30, 33-47, 51 and 55-57 were/stand cancelled. Claims 1-3, 11-12, 15, 18-19, 22, 26-27, 29, 31-32, 48-50 and 52-54 are pending.
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 .
Priority
This application is a 371 of PCT/US2022/077969 (10/12/2022) which claims benefit of 63/254,808 (10/12/2021) as reflected in the filing receipt issued on July 18 2025.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 10 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3, 26-27 and 31-32 are rejected under 35 U.S.C. 101 because the claimed invention is directed to laws of nature and a natural phenomenon without significantly more.
The claims recite laws of nature and natural phenomena. These judicial exceptions are not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception as explained below:
Subject Matter Eligibility Guidance
A three-step inquiry has been established to determine subject matter eligibility under 35 U.S.C. 101, in accordance with MPEP § 2106:
Step (1). Is the claim directed to a process, machine, manufacture, or composition of matter?
Step (2A). Is the claim directed to a law of nature, natural phenomenon (product of nature), or an abstract idea?
Prong 1 – Does the claim recite a law of nature, natural phenomenon, or an
abstract idea?
Prong 2 – If the claim recites a judicial exception, does it recite additional elements that integrate the judicial exception into a practical application?
Limitations that are indicative of integration into a practical application include:
Improvements to the functioning of a computer, or to any other technology or technical field. See MPEP § 2106.05(a)
Applying the judicial exception with, or by use of, a particular machine. See MPEP § 2106.05(b)
Effecting a transformation or reduction of a particular article to a different state or thing. See MPEP § 2106.05(c)
Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. See MPEP § 2106.05(d)
Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception. See MPEP § 2106.05(e)
Step (2B). If the recited judicial exception is not integrated into a practical application, does the claim recite additional elements that amount to significantly different than the judicial exception such that they provide an inventive concept? This step includes evaluation of the same considerations under Step (2A), Prong 2, as well as two additional considerations:
Adding a specific limitation or combination of limitations that are not well-understood, routine, conventional activity in the field, which is indicative that an inventive concept may be present; and
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, which is indicative that an inventive concept may not be present.
Analysis
Step (1): The answer to this step is yes since claims 1-3, 26-27 and 31-32 are directed to antisense oligonucleotides which are a product, which is a statutory category.
Step (2A):
Product of Nature Definition
When a law of nature or natural phenomenon is claimed as a physical product, the courts have often referred to the exception as a "product of nature". See Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 580, 106 USPQ2d 1972, 1975 (2013); University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 758-59, 113 USPQ2d 1241, 1243 (Fed. Cir. 2014). As explained in those decisions, products of nature are considered to be an exception because they tie up the use of naturally occurring things, but they have been labeled as both laws of nature and natural phenomena. See Myriad Genetics, Inc., 569 U.S. at 590-91, 106 USPQ2d at 1979.
Claim Analysis
Prong 1
The markedly different characteristics analysis is part of Step 2A Prong One, because the courts use this analysis to identify product of nature exceptions.
Claims 1-3, 26-27 and 31-32 are directed to antisense oligonucleotides which are just short chains of DNA or RNA. While the sequences as claimed are complementary to an intron of complement C5 pre-mRNA, they still amount to short chains of DNA or RNA as claim 26 recites the oligonucleotide can be single stranded or double stranded. Claim 27 indicates that the bases can be thymine nucleobases or uracil nucleobases. Nothing indicates that the rejected claims exhibit any markedly different characteristics from its naturally occurring counterpart. Note: MPEP 2106.04(b).
Therefore, the answer to step 2A prong 1 is yes.
If the claim includes a nature-based product that does not exhibit markedly different characteristics from its naturally occurring counterpart in its natural state (as established above), then the claim recites a "product of nature" exception, and requires further analysis in Step 2A Prong Two to determine whether the claim as a whole integrates the exception into a practical application.
Prong 2:
The Prong Two analysis considers the claim as a whole. That is, the limitations containing the judicial exception as well as the additional elements in the claim besides the judicial exception need to be evaluated together to determine whether the claim integrates the judicial exception into a practical application. Here while claim 48 integrates the natural product into a practical application, the above rejected claims do not as only claim 32 includes additional elements other than the natural product and this claim does not integrate the natural product into a practical application.
Therefore, the answer to step 2A prong 2 is No.
Step (2B):
Instant claims 1-3, 26-27 and 31 do not recite any additional elements other than the natural product. Claim 32 while reciting a carrier and/or excipient, this includes water. Since nucleic acids are found in cells which contain water, the additional element recited in claim 32 does not distinguish from the naturally occurring product.
Therefore, the answer to step (2B) is No.
Conclusion
Claims 1-3, 26-27 and 31-32 are directed to a judicial exception and do not qualify as eligible subject matter under 35 U.S.C. § 101.
Claim Rejections - 35 USC § 112-Indefinite
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 52-54 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.
Claims 52-54 as currently written is vague and indefinite. The claims recite in line 1 “The method of claim 1”. However, claim 1 isn’t a method but claim 1 is directed to An antisense oligonucleotide. Thus, the claims lack antecedent basis for the recitation “The method”.
Claim 52 recites the limitation "the subject" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 52 depends from claim 1 and does not recite a subject. Perhaps Applicants meant for claim 52 to depend from claim 48.
Claim 53 recites the limitation "the subject" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 53 depends from claim 1 and does not recite a subject. Perhaps Applicants meant for claim 53 to depend from claim 48.
Claim 54 recites the limitation "the pharmaceutical composition" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 52 depends from claim 1 and does not recite a pharmaceutical composition.
Claim 54 as currently written is vague and indefinite. The claim recites the active method step of “is administered” but this claim depends from claim 1 which is a product claim and claim 54 is indefinite as it isn’t clear if the claim is directed to a method or the product. Per MPEP 2173.05(p): A single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. See In re Katz Interactive Call Processing Patent Litigation, 639 F.3d 1303, 1318, 97 USPQ2d 1737, 1748-49 (Fed. Cir. 2011).); Ex parte Lyell, 17 USPQ2d 1548 (Bd. Pat. App. & Inter. 1990).
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.
Claim(s) 1-3, 26-27 and 31-32 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Naito et al. (USPGPUB No. 20080113351).
The instant application claims an antisense oligonucleotide comprising a sequence that is complementary to an intron of complement C5 pre-MRA. As claimed this oligonucleotide comprises at least 10 contiguous nucleotides of a nucleic acid sequence as set forth in any one of SEQ ID NO: 1-150.
Naito et al. is directed to polynucleotides for causing RNA interference and method for inhibiting gene expression using the same. Claimed is a pharmaceutical composition which comprises a pharmaceutically effective amount of the polynucleotide (claim 18). Polynucleotides consist of the base sequence shown in any of SEQ ID NO: 47 to 817081 (claim 7).
As shown below SEQ ID NO: 436907 has at least 10 contiguous (11 nt total) nucleotides of SEQ ID NO: 154.
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653
1166
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And therefore the sequence (SEQ ID NO: 436807, Db) has 11 contiguous nucleotides of SEQ ID NO: 4 (Qy, Intron 3):
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372
676
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Regarding the recitation “complementary to an intron of a complement C5 pre-mRNA”, while Naito et al. does not expressly use this language, the sequence is expressly taught for RNA interference. Since the sequence expressly taught meets the structural requirements as set forth in the claim, it anticipates the claim.
Where selection of one named species from a list of alternatives is all that isrequired to arrive at the instantly claimed subject matter, that species is anticipated. Ex Parte A., 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990). See also In re Sivaramakrishnan, 213 USPQ 441 (CCPA 1982). MPEP 2131.02
Regarding claim 32, Naito et al. claims a pharmaceutical composition. It is taught that the pharmaceutical composition includes a pharmaceutically acceptable carrier which is blended with the polynucleotide (claim 272).
Claim(s) 1-3, 26-27 and 31-32 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by McSwiggen et al. (USPGPUB No. 20050124567).
The instant application claims an antisense oligonucleotide comprising a sequence that is complementary to an intron of complement C5 pre-MRA. As claimed this oligonucleotide comprises at least 10 contiguous nucleotides of a nucleic acid sequence as set forth in any one of SEQ ID NO: 1-150.
McSwiggen et al. is directed to RNA interference mediated inhibition of TRPM7 gene expression using short interfering nucleic acid (siRNA). Claimed is an siRNA comprising any of SEQ ID NO: 1-926 (claim 33). As shown in Table II, a specific siRNA corresponds to SEQ ID NO: 119.
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176
995
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55
988
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As shown below, SEQ ID NO: 19 has at least 10 contiguous (11 nt) nucleotides complementary to a nucleic acid sequence set forth in SEQ ID NO: 161.
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520
784
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And therefore contains at least 10 contiguous (11 nt) nucleotides of SEQ ID NO: 11 (Qy, Intron 5):
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357
659
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Regarding the recitation “complementary to an intron of a complement C5 pre-mRNA”, while McSwiggen et al. does not expressly use this language, the sequence is expressly taught for RNA interference. Since the sequence expressly taught meets the structural requirements as set forth in the claim, it anticipates the claim.
Where selection of one named species from a list of alternatives is all that isrequired to arrive at the instantly claimed subject matter, that species is anticipated. Ex Parte A., 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990). See also In re Sivaramakrishnan, 213 USPQ 441 (CCPA 1982). MPEP 2131.02
Regarding claim 32, McSwiggen et al. claims a pharmaceutical composition. A composition comprising the siRNA together with a pharmaceutically acceptable carrier is claimed (claim 34).
Claim Rejections - 35 USC § 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 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-3, 11-12, 15, 18-19, 22, 26-27, 29, 31-32, 48-50 and 52-54 are rejected under 35 U.S.C. 103 as being unpatentable over van Ommen et al. (USPGPUB NO. 20120259002) in view of Kamola et al. (Nucleic Acids Research, 2015).
Applicant Claims
The instant application claims an antisense oligonucleotide comprising a sequence that is complementary to an intron of complement C5 pre-MRA.
The instant application claims a method of treating a disease or disorder associated with complement C5 dysfunction of complement C5 in a subject, the method comprising administering an effective amount of the antisense oligonucleotide.
The examiner notes that the BRI of the recitation “optionally” is that the limitations are not required to be present. Every limitation following “optionally” is not a required limitation and therefore the prior art does not teach to teach or suggest.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Van Ommen et al. is directed to a molecule for treating an inflammatory disorder. Taught are antisense oligonucleotides (AON) (paragraph 0006). Taught that is possible to use an AON which comprises an intron specific sequence. Such AON comprise a sequence which is complementary to a non-exon region of a C5. An AON is preferably complementary to at least part of a C5, respectfully IL-TRAcP exon and/or intron and said part having 8-20 nucleotides or more (paragraph 0011). Taught an oligonucleotide that comprises or consist of a sequence which complementary to or bind intron 17 of C5 pre-mRNA. The murine and human pre-mRNA sequence of intron 17 is represented by SEQ ID No: 3 and 4. Therefore, an oligonucleotide preferably complementary to or binds a stretch of at least 8 nucleotides of SEQ ID NO: 3 or 4 (paragraph 0014). Alternatively an oligonucleotide comprises or consists of a sequence which is complementary to or binds human intron 8 or 9 of IL-1RAcp pre-mRNA. A human pre-mRNA sequence of intron 8 and 9 is represented by SEQ ID NO: 62 and 63. (paragraph 0014). As claimed the oligonucleotide comprises a sequence which is complementary to or binds an intronic sequence of C5 (claim 5). As claimed the oligonucleotide comprises one or more 2’-O-methyl phosphorothioate (claim 9). Diseases associated with elevated plasma levels of C5a is known to be associated with many clinical conditions including sepsis, rheumatoid arthritis and Alzheimer’s disease (paragraph 0003; claim 12). Alternatively or in combination with a backbone modification, a nucleic acid may have a sugar modification and/or base modification. Sugar modifications include 2’-O-alkyl. Base modifications include 5-methyl-cytosine (paragraph 0036). As taught are pharmaceutical compositions comprising an oligonucleotide in addition to a carrier, diluent and/or excipient (paragraph 0052). When administering an oligonucleotide and/or an equivalent thereof, it is preferred that an oligonucleotide and/or an equivalent thereof is dissolved in a solution that is compatible with the delivery method. For intravenous, subcutaneous, intramuscular, intrathecal and/or intraventricular administration it is preferred that the solution is a physiological salt solution (paragraph 0045).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Van Ommen et al. suggest that the AON can comprise or consist of a sequence which is complementary to an intron such as intron 17, 8 or 9, Van Ommen et al. does not expressly exemplify this or the claimed sequences or teach gapmers. However, these deficiencies are cured by Kamola et al.
Kamola et al. is directed to the in silico and in vitro evaluation of exonic and intronic off-target effects for a crucial element of therapeutic ASO gapmer optimization. It is hypothesized that ASOs are as likely, if not more so, to interact with intronic sequences as with exonic regions (page 8639, right column, first paragraph). It is taught that the investigation revealed efficient silencing of hits predicted against both exonic and intronic regions, with a wide range of mismatch and/or gap patterns (page 8642, left column). It is taught that intronic regions are markedly more susceptible to ASO silencing than exonic sequences (page 8643, right column). Assay verified knockdown at a mature mRNA level ensuring that the ASO’s interaction with the intron regions results in degradation of the whole transcript (page 8644, left column). The gapmer design of ASOs relies on the activity of RNase H1 to achieve gene knockdown following hybridization to the target transcript RNase H1 activity occurs mainly within the nucleus and there are numerous examples of interaction between ASOs and non-coding sequences (e.g. intron or enhance rRNA targeting ASOs) (page 8646, right column). Designing ASOs specifically against intron regions might provide more potent molecules that would attain therapeutic effect with fewer chemical modifications or at a lower dose. This in turn could reduce potential off-target editing (OTEs) or class toxicities that are only observed at higher doses and/or binding strength. (page 8648, right column). Based on the comparison between exonic and intronic OTEs we also believe that designing RNase H1-utilizing ASOs specifically against introns, while highly influenced by intron characteristics and the splicing mechanism, has the potential to improve therapeutic index and possibly safety (page 8649, left column, last paragraph).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claim 1, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Van Ommen et al. and Kamola et al. and design ASO which target an intronic region of C5. One skilled in the art would have been motivated to target these regions as ASO design targeting these region have the potential to improve therapeutic index as well as safety while still reducing expression of the corresponding mRNA as taught by Kamola et al. Since Van Ommen et al. teaches that the ASO can consist of a sequence which is complementary to an intronic region of C5 there is a reasonable expectation of success.
Regarding claim 2, Van Ommen et al. teaches intronic regions 17, 8 or 9.
Regarding claim 3, Van Ommen et al. teaches an AON is preferably complementary to at least part of a C5, respectfully IL-TRAcP intron and said part having 8-20 nucleotides or more which overlap the range claimed.
Regarding claims 11-12, 16 and 18-19, Van Ommen et al. teaches 2’-O-methyl phosphorothioate which reads on both phosphorothioate linkages as well as 2’-O-methyl modifications.
Regarding claim 22, Kamola et al. teaches gapmers are antisense oligonucleotides which can be used to target introns.
Regarding claim 26, Van Ommen et al. exemplifies single strand ASOs.
Regarding claim 29, Van Ommen et al. teaches the modifications include base modifications such as 5-methylcytosine. It would have been obvious to one of ordinary skill in the art to try any of the specifically taught base modifications as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Regarding claims 27 and 31, at a minimum, Van Ommen et al. teaches an ASO which is complementary to or bind intron 17 which in humans is associated with SEQ ID NO: 4. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Van Ommen et al. and Kamola et al. and design ASO which contain at least 8 but as many as up to 20 or more nucleotides that are complementary to SEQ ID NO: 4.
As shown below SEQ ID NO: 19 (Qy) instantly claimed has 100% complementary identity corresponding to nt 3816-3797 of SEQ ID NO: 4 of Van Ommen et al. (Db)
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672
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Instantly claimed SEQ ID NO: 169 (Qy) has 100% identity to nt 3797-3816 of SEQ ID NO: 4 of Van Ommen et al. (Db):
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675
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Regarding claim 32, Van Ommen et al. teaches composition comprising an oligonucleotide in combination with a carrier and/or excipient.
Regarding claims 48-50 and 52-53, Van Ommen et al. teaches a method for alleviating one or more symptoms and/or characteristics and/or for improving a parameter of an inflammatory disorder in an individual (claim 12). It is generally taught that diseases associated with elevated plasma levels of C5a is known to be associated with many clinical conditions including sepsis, rheumatoid arthritis and Alzheimer’s disease. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Van Ommen et al. and Kamola et al. and administer the ASO to a individual suffering from a disease such as Alzheimer’s disease. Since this is a disease as taught by Van omen et al. associated with elevated plasma levels of C5a, one skilled in the art would have been motivated to deliver an ASO to silence or knock out this gene to reduce the plasma levels. Van Ommen et al. teaches the inflammatory disorder can be in humans (paragraph 0048).
Regarding claim 54, Van Ommen et al. teaches the same administration (intravenous, intramuscular, subcutaneous, etc.).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached on 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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