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 .
The Restriction mailed 9/24/25 is VACATED in favor of this Office Action.
1. Formal Matters
A. Upon further review, all species have been examined.
B. Claims 1-3 and 5-18 are pending and are the subject of this Office Action.
2. Specification
A. When a sequence is presented in a drawing, regardless of the format or the manner of presentation of that sequence in the drawing, the sequence must still be included in the Sequence Listing and a sequence identifier ("SEQ ID NO:X") must be used either in the drawing or in the Brief Description of the Drawings. See MPEP § 2422.02. Sequences are found in at least Figure 14C.
B. If applicable, the first line of the specification should be updated to reflect the status (e.g. “now U.S. Patent No.”, or “now abandoned”) of any parent applications. Similarly, though none could be found, any U.S. or Foreign Applications cited in the specification which have since issued should be updated with the corresponding Patent No.
C. Though none could be found, any listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
D. Though no issues could be found, Applicant is advised that embedded hyperlinks and/or other forms of browser-executable code are impermissible and require deletion. The attempt to incorporate subject matter into the patent application by reference to a hyperlink and/or other forms of browser-executable code is considered to be an improper incorporation by reference. See MPEP 608.01(p), paragraph I regarding incorporation by reference. It is noted that the recitation of “www.” alone, as opposed to “http://www.”, is also active and should not be used.
E. Though no issues could be found, trade names or marks used in commerce should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
F. Though no issues could be found, according to 37 CFR 1.821(d) (MPEP § 2422), where the description or claims of a patent application discuss a sequence listing that is set forth in the "Sequence Listing" in accordance with paragraph (c) of this section, reference must be made to the sequence by use of the assigned identifier, in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application.
G. The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicants’ cooperation is requested in correcting any errors of which Applicants may become aware.
3. Claim Rejections - 35 USC § 112(a) – written description
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3 and 5-18 are rejected under 35 U.S.C. 112, first paragraph, as containing subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention.
These are genus claims. The claims are drawn a method of treating cancer by administering a polynucleotide ligand capable of stimulating a PRR along with a 3E10 antibody having CDRs of SEQ ID NO:16, 17, 18, 24, 25 and 26.
First, Li and Wu (Abstract) teaches that PRRs are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells and that they can be divided into 5 types based on protein domain homology – Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs).
However, of the TLRs, Li and Wu (Table 1; Page 3, right column, 1st paragraph; Figure 1) state -
some TLRs (TLR1, 2, 4, 5, 6, 10) are expressed on the surface of immune cells in the form of heterodimers or homodimers, mainly recognizing the membrane components of pathogenic microorganisms, such as lipids, lipoproteins, and proteins; others (TLR3, 7, 8, 9) are expressed in the form of homodimers, which mainly recognize the nucleic acids of microorganisms
Given this teaching by Li and Wu that only TLRs 3, 7, 8 and 9 bind polynucleotide ligands, as well as Applicants’ specification, it appears that, regarding TLRs, only those recited in claim 8, which are consistent with Li and Wu, are adequately described as binding polynucleotides.
However, while 4 of the 5 groups of PRRs are known to bind polynucleotides (CLRs do not - see Li and Wu. Page 6, right column), a further issue is that claim 1 is drawn to any and all polynucleotides ligands which can bind any of the PRRs and are able to lead to a cancer treatment. However, the sheer number of polynucleotides able to be bound by PRRs, even limited to claimed RIG-I and TLR3, 7, 8 and 9, is immense and includes not only endogenous nucleic acids from numerous types and states of cells, but also from pathogens. The polynucleotide genus consists of a broad range of DNA, single-and double-stranded RNA, including viral RNA, protein-coding and non-encoding RNA, plasmids, vectors, antisense, siRNA and mRNA. In reality, the number of polynucleotides which, when coupled to 3E10, are able to treat cancer is only a fraction of the genus of polynucleotides encompassed by claim 1 and Applicants have not adequately described this genus.
Therefore, the specification and claims, in light of Li and Wu, only show that RIG-1 and TLR3, 7, 8 and 9 are able to bind polynucleotides. However, the specification only adequately describes RIG-1 with poly(I:C) and 3p-hpRNA (e.g. Examples 14 and 16-18). Given the similar characteristics and understanding in the art of poly(dA:dT) compared to poly(I:C), the Examiner has concluded that both poly(I:C) and poly(dA:dT) conjugated to RIG-1 are adequately described, as is the 3p-hpRNA of SEQ ID NO:94 in claim 13, in their potential to treat cancer. In addition, given the teachings of both Goutagny et al. (Table 3) and Shekarian et al. (Table 1), TLR3-poly(I:C) is also adequately described.
Regarding polynucleotides, other than stimulating a PRR, the specification and claims do not indicate what distinguishing attributes are shared by the members of the genus. Thus, the scope of the claims includes numerous structural variants, and the genus is highly variant because a significant number of structural differences between/among genus members is permitted. The specification and claims do not provide any guidance as to what changes should be made. Structural features that could distinguish compounds in the genus from others in the polynucleotide class are missing from the disclosure. No common structural attributes identify the members of the genus.
Therefore, in summary, the general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed. Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, poly(I:C), poly(dA:dT) and SEQ ID NO:94, alone, are insufficient to describe the genus. In addition, given the specification and state of the art, only RIG-1, TLR3, 7, 8 and 9, not all PRRs, are described as potentially involved in cancer treatment via their ligands, with RIG-1 being the only one adequately described in the instant specification. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus. Thus, Applicant was not in possession of the claimed genus at the time the invention was made.
4. Claim Rejections - 35 USC § 112(a) – scope of enablement
Claims 1-3 and 5-9 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for compositions comprising the antibody of claims 1 and 10 linked to a polynucleotide ligand capable of stimulating a PPR, as well as methods of treating cancer using RIG-1 with poly(I:C), poly(dA:dT) and 3p-hpRNA (SEQ ID NO:94) as well as using TLR3-poly(I:C), does not reasonably provide enablement for methods of treating cancer using these compositions. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
In In re Wands, 8USPQ2d, 1400 (CAFC 1988) page 1404, the factors to be considered in determining whether a disclosure would require undue experimentation include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Claims 10-18 are not rejected since, though the preamble recites “for treating cancer”, this is an intended use and does not have patentable weight. Given the knowledge in the prior art, it would not be undue experimentation to form a complex between a polynucleotide to 3E10.
For the rejected claims, the breadth is excessive with regard to claiming methods of treating cancer by using a complex comprising any polynucleotide complexed with any PRR. As discussed above regarding written description, PRRs can be divided into 5 types based on protein domain homology. Of these, only RIG-1, TLR3, 7, 8 and 9 and ALRs have been shown to be able to bind DNA and are associated with cancer.
However, Applicants only provide guidance and working examples of RIG-1 with poly(I:C) and 3p-hpRNA (e.g. Examples 14 and 16-18) for the treatment of cancer. Given the similar characteristics and understanding in the art of poly(dA:dT) compared to poly(I:C), the Examiner has concluded that both poly(I:C) and poly(dA:dT) conjugated to RIG-1 are adequately described, as is the 3p-hpRNA of SEQ ID NO:94 in claim 13, in their potential to treat cancer. In addition, given the teachings of both Goutagny et al. (Table 3) and Shekarian et al. (Table 1), TLR3-poly(I:C), taught to be involved in cancer therapy, is also enabled.
While ALRs, TLR3, TLR7, TLR8 and TLR9 are all known to bind DNA and/or RNA and play a role in suppressing or promoting cancer, Applicants have not provided guidance as to the genus of polynucleotides which can actually bind these receptors which, when complexed to 3E10, can treat cancer, as this genus consists of a broad range of DNA, single-and double-stranded RNA, including viral RNA, protein-coding and non-encoding RNA, plasmids, vectors, antisense, siRNA and mRNA
Given only this minimal guidance, it is not predictable to one of ordinary skill in the art at the time of the instant invention which members of the large genus of PRRs could be targeted, or which of the large genus of polynucleotides could be complexed with PRR in order to treat cancer.
5. Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
A. Claims 1-3, 5, 6, 9-15 and 18 are rejected under 35 U.S.C. 103 as being unpatentable Weisbart et al. (reference C214 on the IDS submitted 10/27/23) in view of Dovgan et al. and further in view of Wu et al.
The claims are generally drawn to treating cancer by administering a complex comprising a polynucleotide ligand capable of stimulating a PRR bound to an antibody having the 6 CDRs of 3E10. Weisbart (Abstract) teaches 3E10 for a potential use in cancer treatment –
A nuclear-penetrating lupus anti-DNA autoantibody, 3E10, has been found to inhibit DNA repair and selectively kill certain cancer cells that are highly vulnerable to DNA damage. In addition, a 3E10 single chain variable fragment (scFv) has been developed for use as a delivery vehicle to carry therapeutic cargo proteins into cell nuclei.
As taught by pages 19-20 of Applicants’ specification regarding Zack et al. (cited as reference C236 on the IDS submitted 10/27/23), it is noted that 3E10 comprises the instantly claimed CDRs. Zack is not being used as part of the rejection, but only to show the sequence of 3E10 as taught by Weisbart.
Weisbart also teaches that this antibody can be linked to a therapeutic cargo, but does not specifically state that the cargo is a polynucleotide.
However, Dovgan does teach antibody-oligonucleotide conjugates for targeted therapeutic delivery (entire document). Given this, it would have been obvious to have linked the oligonucleotide cargo of Dovgan to the 3E10 antibody of Weisbart, especially given that both conjugates are essentially the same and serve essentially the same purpose.
None of the above references teach targeting a PRR. However, Wu teach targeting cancer by activating RIG-1 with various polynucleotides (e.g. Table 1).
Given these references as a whole, it would have been obvious to have targeted the RIG-1 PRR in cancer cells, as taught by Wu, by conjugating the 3E10 antibody of Weisbart with the oligonucleotide cargo of Dovgan.
B. Claims 7, 8, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Weisbart et al. in view of Dovgan et al. and further in view of Wu et al. and further in view either (1) Goutagny et al. or (2) Shekarian et al.
The claims are rejected under 35 USC 103 insofar as they read on TLR3, as the genus of TLR is rejected above under 35 USC 112(a) regarding scope of enablement.
The teachings of Weisbart, Dovgan and Wu are seen in paragraph A of this section. None teach TLR3. However, both Goutagny et al. (Table 3) and Shekarian et al. (Table 1) teach a complex comprising TLR3-poly(I:C), which they teach is involved in cancer therapy.
7. Conclusion
No claim is allowable.
Advisory information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT S LANDSMAN whose telephone number is 571-272-0888. The examiner can normally be reached M-F 8 AM – 6 PM (eastern).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ROBERT S LANDSMAN/Primary Examiner, Art Unit 1647