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 .
Claim Status
Receipt is acknowledged of the amendments to the claims submitted on 02 September 2026. Claims 16-25 are amended.
Applicant’s election without traverse of the invention of group I (claims 1-7) in the reply filed on 02 September 2026 is acknowledged. Applicant has also amended claims 16-25 to depend from the elected group and requested rejoinder of the invention of group III (claims 16-25). Claims 16-25 are rejoined with claims 1-7 for prosecution.
Claims 8-15, and 26-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
It is noted that Applicant has failed to properly label claims 8-15, and 26-30 as withdrawn in the response submitted on 02 September 2026. Applicant should be aware that, upon election, whether with or without traverse, Applicant should properly label pending claims as withdrawn when they do not read on the elected invention. See 37 C.F.R. 1.142.
Therefore, claims 1-30 are pending and claims 1-7, and 16-25 are under examination in the present Official Action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2023/057637, filed 24 March 2023, which claims priority to EP Application Nos. EP22210726.0, filed 01 December 2022, and EP22164337.2, filed 25 March 2022. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copies of papers required by 37 CFR 1.55 have been filed in this application on 19 September 2024.
The earliest possible priority for the instant application is 25 March 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 22 October 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings submitted on 19 September 2024 are accepted by the Examiner.
Claim Objections
Claims 6 and 25 are objected to because of the following informalities: abbreviations/acronyms need to be spelled out upon their first encounter in the claims (for example: “SHP”). Appropriate correction is required.
Claim 24 is objected to because of the following informalities: Because a SEQ ID NO is a placeholder, claim 24 should be amended to refer to “each of said antigen-binding moieties comprises the polypeptide of SEQ ID No. 35 and the polypeptide of SEQ ID No. 36”. Appropriate correction is required.
Claims 2, 3, 4, 5, 6, 7, and 16 are objected to because of the following informalities. Each of these claims refers to the product (recombinant adenovirus) of a preceding claim by use of an indefinite article “An” or “A” or “a”. The use of an indefinite article in this context is grammatically incorrect, i.e. the definite article --the-- should be used in this context. For example, “A recombinant adenovirus according to claim 1 (claim 2) should be --The-- “recombinant adenovirus according to claim 1”. 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 1-7, and 16-25 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.
Claims 1, 2, 3, 4, 20, 21, and 22 are indefinite in their recitation of “a functional interleukin 2 polypeptide”, as it is unclear as to “the function” or functions that are intended as being encompassed by the noted phrase. Proteins are known in the prior art to have numerous activities, both specific and general. For example, all proteins of a sufficient length are known to have the activity of eliciting an antibody or immune response. It is suggested that applicant clarify the intended meaning of the noted phrase.
Claim 2 recites the limitation "the knob of said adenovirus" in the third line of the claim. There is insufficient antecedent basis for this limitation in the claim. Nowhere in claim 2 nor claim 1 from which claim 2 depends recites “a knob of said adenovirus”. In addition, it appears that Applicant is attempting to refer to a knob of a fiber protein of said adenovirus. If this is the intention, Applicant should amend the claim accordingly. Claims 3, 21, and 22 recite similar recitations of “the knob” in lines 6, 6, and 11 respectively and, consequently, also are indefinite for lacking proper antecedent basis. Claims 5-7, and 23-24 are further rejected for their dependency on a rejected base claim.
Claims 5, and 23 recite “a knob of an adenovirus” in the third line and fourth line of the claims respectively. Each claim depends from a prior claim which recites “the knob” (claim 5 depends from claim 3 and claim 23 depends from claim 22). Therefore, it is unclear whether Applicant intends claims 5 and 23 to refer to the same “knob” or a distinct “knob” from the claims from which they depend respectively. Consequently, a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought.
Claims 18, 19 and 25 are indefinite in their recitation of “preferably” because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 17 is vague and indefinite in the recitation of “…capable of…” , since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention.
Note, it has been held that the recitation that an element is “capable of” performing a function is not a positive limitation, but only requires the ability to so perform. It does not constitute a limitation in any patentable sense. In re Hutchinson, 69 USPQ 138.
Claim 25 is vague and indefinite because it recites the phrase "derived from" and the metes and bounds of how a trimerization domain can be "derived from" the capsid protein SHP of lambdoid phage 21and still meet the intended limitation of the claim are not clear. It is not possible to know the metes and bounds of a "derivative" because any given starting material can have many divergent derivatives depending on the process of derivatization. This rejection could be overcome by substituting "isolated" for "derived" in the claim.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-7, and 16-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
The claims broadly encompass a genus of adenoviruses comprising any adenovirus (Any known and any yet to be discovered species of adenovirus) displaying a functional interleukin 2 polypeptide by any means (designed ankyrin repeat domain (DARPin) or direct genetic fusion to protein IX, hexon protein, fiber protein (any portion), or penton base protein). The claims at least require the IL-2 to be able to be displayed while simultaneously retaining its functional characteristics and they also require the recombinant adenovirus to be capable of transducing T cells. The claims do not recite sufficient structure corresponding to these functions. Therefore, there is insufficient structure/function relationship in the claims.
The specification provides only two examples of a polypeptide comprising IL-2 displayed on an adenovirus (Example 1, SEQ ID NO: 6 and 7). Each of these sequences possesses an identical DARPin sequence (SEQ ID NO: 2) and an identical trimerization domain (SEQ ID NO: 1). Further, the trimerization domain is the capsid protein SHP of lambdoid phage 21 (claims 6-7) and the adenovirus disclosed in the working examples is a human C5 adenovirus (HAdV-C5) (Specification, [0760]). Neither of these sequences (SEQ ID NO: 6 and 7) alone was able to transduce T cells at a frequency of more than 3% (Specification, [0779]-[0781], FIG. 1). However, when T cells were activated with Dynabeads (CD3/CD28) and recombinant IL-2 simultaneously with adenoviruses expressing the polypeptides around 80% transduction was achieved (Specification, [0782]-[0784]). The specification also teaches an anti-CD3 adapter and an anti-CD28 adapter which each possess identical DARPin sequences and trimerization domains to SEQ ID NOs: 6 and 7 (Specification, [0776]-[0777]). Nowhere in the specification is a DARPin other than that of SEQ ID NO: 2 used to display a functional IL-2 protein on an adenovirus and nowhere is an adenovirus other than C5 adenovirus used to accomplish the display. In addition, the working examples teach no examples in which T cells were able to be transduced with anything other than C5 adenovirus displaying a polypeptide having the amino acid sequence of either SEQ ID NO: 6 or SEQ ID NO: 7. Thus, Applicant has only disclosed one species of adapter protein utilizing only a single species of DARPin and a single species of trimerization domain capable of facilitating the display of a functional IL-2 polypeptide (either SEQ ID NO: 6 or 7) on an adenovirus and only one species of recombinant adenovirus (recombinant C5 adenovirus) displaying a functional IL-2 polypeptide with the functional property of being capable of transducing T cells. Where anti-CD3 and anti-CD28 adapters are taught, they also require the DARPin of SEQ ID NO: 2 and the specific trimerization domain to enable the functional properties claimed (SEQ ID NOs: 8 for anti-CD3 and 9 for anti-CD28).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). Further, A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). See MPEP 2163(II)(A)(3)(a)(ii).
In this case, the limitation of the working examples to only a single species of adapter protein fused to only two specific IL-2 polypeptides and displayed on a human C5 adenovirus having the claimed functional properties does not represent to the skilled artisan in the field of adenoviral display that Applicant had possession of a representative number of species at the time of filing. In view of the limited supporting disclosure, the breadth of the claims appears to be less of a demarcation of the outer limits of the genus possessed by Applicant and more of a prompt to the skilled artisan to go forth and discover other recombinant adenoviruses possessing the claimed functions.
While numerous DARPins which bind to various targets are known, only one is known which binds to the knob protein of adenovirus and which has been fused to a functional peptide for display of the functional peptide and transduction of specific cells (Dreier et al., Proceedings of the National Academy of Sciences of the United States of America vol. 110,10 (2013): E869-77, hereinafter "Dreier", of record on the IDS submitted 22 October 2024). Of note, the Dreier reference shares inventorship with the instant application. Dreier teaches the state of the art with regard to DARPins targeting adenovirus fiber knob proteins (Dreier, “Introduction”). Dreier teaches the redirection of the tropism of C5 adenovirus by ablating its natural tropism through mutations to the knob protein and introducing a trimeric DARPin adapter that targets the mutant knob protein (Dreier, Abstract, page E869, fourth-sixth paras.). Dreier teaches that the trimeric DARPin adapter used an unusually stable trimerization domain, SHP of the lambdoid phage 21 which clamped the knob so tightly that they become an integral structural component of the virus (Dreier, page E870, first partial para.). Dreier teaches the fusion of this adapter to DARPins specific for human biomarkers to target C5 adenovirus to transduce specific cells (Dreier, page E870, first partial para.). Thus, to the extent the skilled artisan at the time of filing knew of the use of DARPins to bind knob protein and to facilitate the display of a functional peptide, this knowledge was limited to C5 adenovirus, lambdoid phage 21 SHP and a DARPin which specifically binds to the knob domain of the C5 adenoviral fiber protein. The skilled artisan knew from Dreier that the combination of the unusually stable trimerization domain SHP of the lambdoid phage 21 with the specific DARPin targeting knob was particularly relevant to the success of the system. At the time of filing, it was known that most experimental and clinical studies have focused on the well-studied species C adenovirus (HAdV-C5) (Baker et al., Nature communications 10.1 (2019): 741, hereinafter "Baker", "Introduction" first para.). Baker teaches that among 56 different serotypes of adenovirus, there is great diversity in the sequence of the fiber-knob protein (Baker, "Results" first para., Fig. 1). Notably, there was great diversity at the interspecies level and at the intraspecies level with adenoviruses in species D generating a greater number of phylogenetic subgroups than the whole genome tree (Baker, "Results" first para.). Thus, the skilled artisan at the time of filing knew that the knob protein of adenoviruses is highly diverse and variable even within species depending on the adenovirus being used.
Accordingly, in view of the art at the time of filing, the claimed genus encompasses enumerable inoperable embodiments insofar as the genus claimed encompasses any species of adenovirus having the claimed functional properties with the use of a DARPin designed to target the knob region of the fiber protein of a disparate species of adenovirus in a region lacking homology to the same protein of the displaying adenovirus. Further, the art at the time of filing evidences unpredictability in the use of any method of display on the surface of adenoviruses of any species of IL-2 to produce a recombinant adenovirus having the claimed functional properties. This is because the art at the time of filing was limited to a single knob targeted DARPin in combination with the unusually stable trimerization domain SHP of the lambdoid phage 21 as an adapter polypeptide for the surface display of peptides on human C5 adenovirus exclusively.
Therefore, in view of the breadth of the genus claimed, the limitation of the working examples to only two recombinant adenoviruses (both human C5 adenovirus) displaying only two different IL-2 proteins fused to only a single species of adapter protein (SEQ ID NO: 6 or 7) alongside only a single anti-CD3 or a single anti-CD28 adapter protein (SEQ ID NO: 8 or 9), and the unpredictability evidenced by the art at the time of filing, the supporting disclosure would not represent to the skilled artisan that Applicant had possession of a representative number of species for the vast genus claimed.
Additional Comments
Dreier appears to be the closest prior art to the instant invention. While Dreier et al. teaches the use of a similar adapter polypeptide to target human C5 adenoviruses to specific cell types (Dreier, page E870, first partial paragraph), Dreier does not teach, suggest, or provide a motivation to display IL-2. In addition, Dreier does not teach the DARPin encoded by instant SEQ ID NO: 2 (found within instant SEQ ID NOs: 6 and 7 identified above as the only species adequately described). Couple this with the relative lack of teachings in the art at the time of filing (see above rejection under 35 U.S.C. 112(a)), and it would hardly seem tenable to argue that it would have been prima facie obvious to a person having ordinary skill in the art to have fused any peptide including IL-2 to arrive at the invention identified as adequately described in the 112(a) rejection above. This is because to do so would have involved a level of unpredictability that precludes a prima facie finding of obviousness.
US20230039976 (hereinafter “Simpson”) teaches an IL-2 having an identical sequence to the instant SEQ ID NO: 5 (reference SEQ ID NO: 4).
US5696234 (hereinafter “Zurawski”) teaches an IL-2 having an identical sequence to the instant SEQ ID NO: 4 (reference SEQ ID NO: 1).
US20080305119 (hereinafter “Dewhurst”) teaches a trimerization domain having an identical sequence to instant SEQ ID NO: 1 (reference SEQ ID NO: 41).
US20200182882 (hereinafter “Lee”) teaches an anti-CD3 TCR having identical CDRs to those of instant SEQ ID NOs: 12-17 (Reference Table 1).
US20220017637 (hereinafter “Gasser”) teaches an anti-CD28 antibody sequence having identical CDRs to those of instant SEQ ID NOs: 19-24 (Reference Table B).
Instant SEQ ID NO: 2 (identified in the adequately described claim scope in the above rejection under 35 U.S.C. 112(a)) appears to be free of the prior art of record. It is noted that SEQ ID NO: 2 alone is not enough to overcome the above rejection for lack of written description support above because both the instant specification and the art at the time of filing evidence unpredictability outside of recombinant human C5 adenoviruses displaying proteins having the amino acid sequence of SEQ ID NOs: 6 or 7 (which each comprise SEQ ID NO: 2).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
