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 .
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 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.
Priority
The instant application, filed 03/15/2024, is a 371 filing of PCT/US2022/043711, filed 09/15/2022, and claims domestic benefit to US provisional application 63/245,135, filed 09/16/2021.
Status of Claims/Application
The preliminary amendment of 03/15/2024 is acknowledged. Claims 17 and 19 are amended. Claims 1-27 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/15/2024 and 08/13/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Interpretation
Claim 1 recites an isolated nucleic acid sequence as set forth in SEQ ID NO: 13 or 14 or a sequence “having 90% identity thereto.” As written, the claim is interpreted as limiting the nucleic acid sequence to one that has exactly 100% or exactly 90% identity to one of the instantly claimed sequences without including any percent identity in between.
Claim Objections
Claim 21 is objected to for the following informality: line 3 of the claim recites “PDD-L2 inhibitor”. There is no art recognized immune checkpoint “PDD-L2”. The recitation appears to be a typographical error for “PD-L2”. Appropriate correction/clarification is required.
Claim 25 is objected to for the following informality: line 2 of the claim recites “SEQ 6 and 7”. Correction to “SEQ ID NO: 6 and 7” is required.
Claim Rejections - 35 USC § 112(b)
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 10 and 16 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.
Claim 10 recites the limitation “wherein SEQ ID NO: 4, 17, or 18 and 6 or 7 are linked by SEQ ID NO: 5 or SEQ ID NO: 17”. There is insufficient antecedent basis for SEQ ID NOs: 17 or 18 being linked to SEQ ID NOs: 6 or 7. The claim depends on claim 8, which does not include SEQ ID NOs: 17 or 18 linked to SEQ ID NOs: 6 and 7. Rather, claim 8 recites SEQ ID NOs: 4, 21, or 22 as being operably linked to 6 and 7 or 7 and 6. It is noted that the recitation of SEQ ID NOs: 4, 17, or 18, in claim 10 maybe a typo and intended to be SEQ ID NOs: 4, 21, or 22. For instance, SEQ ID NO: 17 is also recited in the second line of claim 10 as a linker and SEQ ID NO: 18, which is recited in claim 18, is a nucleic acid sequence.
Appropriate correction/clarification is required.
Claim 16 depends on claim 15, which depends on claim 14, and ultimately on claim 8 and recites the limitation “the protein”. The only explicit reference to a protein in the claim, or the claims upon which it depends, is “the fusion protein”. The claims also recite sequences that are amino acids and could be interpreted as being referenced by the limitation. As it is unclear which protein is being referenced, the metes and bounds of the claim are indefinite. MPEP 2173.05(e) states “if two different levers are recited earlier in the claim, the recitation of "said lever" in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended.“
In the instant office action, the claim is interpreted as limiting the recitation of “SEQ ID NO: … 4, 21, or 22” in claim 8 to being SEQ ID NO: 21 or 22.
Claim Rejections - 35 USC § 112d
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 11, 14, and 16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 11 recites the limitation “wherein SEQ ID NO: 6 and 7 are in operable linkage in either order.” The claim depends on claim 8, which recites a fusion protein comprising in operable linkage… “6 and 7 or 7 and 6.” As such, claim 8 already includes SEQ ID NOs: 6 and 7 operably linked in either orientation and; therefore, claim 11 does not act to further limit the claim upon which it depends.
Regarding claim 14, the claim depends on claim 8 and recites the limitation “wherein SEQ ID NO: 4 has an N72 substitution.” Claim 8 recites that the fusion protein comprises, in operable linkage, SEQ ID NO: 2 or 23; 4, 21, or 22, and 6 and 7 or 7 and 6. Claim 8 requires that the sequence referenced in claim 14 be SEQ ID NO: 4 and; therefore, claim 8, which allows for the substitution of any amino acid in position N27, is broader than the claim upon which it depends and also doesn’t include all of the limitations of the claim upon which it depends.
Regarding claim 16, the claim recites the limitation that the protein is set forth in SEQ ID NO: 21 or 22. Claim 16 depends on claim 15 which limits the N72 mutation in claim 14 to being N72A or N72D.
SEQ ID NOs: 21 and 22 are sequences that are identical to instant SEQ ID NO: 4 with the exception of a N72D and N72A substitution, respectively. As making the substitutions recited in claim 15 would result in sequences that are identical to those recited in claim 16, claim 16 fails to limit the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)- 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 19-22 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 therapeutic treatment, does not reasonably provide enablement for prophylactic/preventative measures. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or 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. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
The instant claims are drawn to a method of treating cancer in a subject comprising administering to the subject a fusion protein of claim 4.
The breadth of the claims
The claims are broad in that they encompass prophylactic/preventative measures.
The instant specification defines treatment as “[t]he term ‘treatment’ is used interchangeably herein with the term “therapeutic method” and refers to both 1) therapeutic treatments or measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic conditions or disorder, and 2) and prophylactic/ preventative measures. Those in need of treatment may include individuals already having a particular medical disorder as well as those who may ultimately acquire the disorder (i.e., those needed preventative measures).” (page 23, [0104]).
The specification does not explicitly define “prophylactic” or “prevention”. In absence of a limiting definition by the applicants, “prevention” is interpreted as defined according to IIME as provided in Wojtczak, A. (2002) Glossary of Medical Education Terms Medical Teacher 24(4): 357; 1-25. IIME defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (page 16, “Prevention”). IIME states that “primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe.” IIME states that “secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health”. IIME further states that tertiary prevention consists of the measures available to reduce or eliminate long-term impairments and disabilities, minimize suffering caused by existing departures from good health”.
Thus, in its broadest reasonable interpretation, the prevention of a condition suggests that that the onset of the condition never occurs and the patient’s health is protected and preserved.
The amount or direction provided by the inventor / the existence of working examples
The instant disclosure does not provide any working examples in which cancer prevention or the use of the claimed fusion protein as a prophylactic treatment is demonstrated.
Additionally, the disclosure does not disclose, or demonstrate through working examples, a method that can be used by one of ordinary skill in the art to predictably determine that a subject would develop cancer in order to establish that cancer was prevented using the claimed method.
The state of the prior art / the level of predictability in the art
There are no art recognized methods that can be used to predictably determine that cancer onset was prevented using claimed method or to identify patients who would predictably develop cancer in order to predictably identify that prevention was achieved using the claimed method. Rather, the state of the art indicates that cancer development was not predictable.
Lewandowska, A.M., et al (2017) Environmental risk factors for cancer – review paper Ann. Agric. Environ. Med. 26(1); 1-7 teaches that the cancerous process is a result of disturbed cell function. This is due to the accumulation of many genetic and epigenetic changes within the cell, expressed in the accumulation of chromosomal or molecular aberrations, which leads to genetic instability. It is difficult to assess the validity of individual etiological factors, but it can be concluded that interaction of various risk factors has the largest contribution for the development of cancer. Environmental, exogenous and endogenous factors, as well as individual factors, including genetic predisposition, contribute to the development of cancer (page 1, right column, paragraph 1). Lewandowska discusses numerous factors that contribute to the development of cancer including physical factors such as exposure to electromagnetic fields, ionizing radiation, and ultraviolet radiation (pages 2-3); chemical factors including tobacco smoking, alcohol, and other chemicals (pages 3-4); and biological factors including diet, physical activity, mutagenic and carcinogenic compounds in food, nitrosoamines, and infections (pages 4-5). Lewandowska teaches that, additionally, some epidemiological research suggests that the influence of environmental factors will further affect the cell’s genetic material. This is connected with the spreading of carcinogens in various geographical zones. While some are well known and can be modified, there are certain factors that cannot be fully controlled, such as industrialization (page 6, left column, paragraph 2).
The teachings of Lewandowska demonstrate that, while it was known that cancer is caused by disturbed cell function, numerous factors had been identified that could lead to such disfunction and cell disfunction is likely caused by the interaction of various risk factors. Lewandowska also teaches factors such as genetic predisposition and environmental factors that can contribute to the formation of cancer but are beyond the control of an individual subject. These teachings demonstrate that there was no specific known cause of cancer and, therefore, suggest that there would be no method to predictably determine that cancer would have developed in order to establish that it was prevented.
Cuzick, J. (2017) Preventive therapy for cancer Lancet Oncol 18; e472- e482 teaches the use of therapeutic preventative measures in addition to weight control and physical activity, such as low-dose aspirin for adults without the risk of hypertension or gastrointestinal bleeding, universal HPV vaccination, and other therapies such as anti-oestrogen drugs for breast cancer prevention targeting high-risks groups to “maintain a favorable benefit-risk ratio” (abstract). While Cuzick is identifying therapeutic regimens to prevent cancer, Cuzick also teaches “the balance of risks and benefits is inherently more challenging for preventative than for therapeutic interventions. Only a small fraction of the apparently healthy people who receive a preventative treatment would ultimately develop the specific type of cancer being targeted. Moreover, the absence of the cancer is not quantifiable at an individual level, whereas all those treated will incur a risk of side-effects which are identifiable on an individual basis” (page e472, left column, paragraph 2).
Cuzick demonstrates that the prevention of cancer is not predictable and that numerous factors contribute to the development of cancer. Additionally, Cuzick teaches difficulties in preventing cancer with therapeutic methods and specifically states that the absence of cancer is not quantifiable on an individual level, a statement which demonstrates that the determination of whether or not cancer was prevented is unpredictable.
DeCensi, A., et al (2015) Barriers to preventative therapy for breast and other major cancers and strategies to improve uptake ecancer 9(595); 1-12 teaches that the global cancer burden continues to rise but the utilization of preventative therapy has been poor due to various barriers. DeCensi teaches barriers such as the lack of physician and patient awareness, fear of side effects, and licensing and indemnity issues. DeCensi provides a review discussing the barriers and proposes strategies to overcome them including improving awareness and countering prejudices by highlighting the important differences between preventative therapy and cancer treatment. DeCensi further teaches that future research to improve therapeutic cancer prevention needs to include improvements in the prediction of benefits and harms and improvements in safety profiles of existing agents by experimentation with dose (abstract). DeCensi teaches that for preventative therapy, we cannot identify individuals whose cancer was prevented or risk was substantially reduced because of the lack of measurable biomarkers of efficacy that currently exist for other diseases such as cardiovascular diseases, prevention of diabetes complications or osteoporotic bone fractures. Therefore, from that person’s point of view, they either took medication unnecessarily or, in the worst-case scenario, unnecessarily suffered the adverse effects of such therapy (page 2, paragraph 1).
The teachings of DeCensi demonstrate that, while preventative therapies could be beneficial if various barriers are overcome, there was no method known that could be used to identify individuals whose cancer was prevented because of the lack of measurable biomarkers.
The teachings of Lewandowska, Cuzick, and DeCensi demonstrate that there was no art recognized method of determining whether a patient would predictably develop cancer and, therefore, there is no predictable way to determine that cancer was prevented using the claimed method.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed above, there is no disclosed or art recognized method through which an ordinarily skilled artisan would be able to determine that a mammal would have predictably developed cancer in order to apply the claimed treatment as a preventative measure. Furthermore, there is no known or disclosed method that could be used to establish that cancer was prevented as there is no predictable way to know that the subject being treated would have developed a cancer without the treatment. As such, in order to implement the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to identify a method that could be used to establish that cancer was prevented, with the possibility that no such method could be found.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 17, 19, and 22 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO 2017/106453 A1 (Ostrand-Rosenberg, S. and D.L. Carter) 22 June 2017.
WO’453 teaches a fusion proteins for use in cancer therapy, specifically, a bispecific T cell engager recombinant polypeptide comprising an antibody, fragment thereof, or single chain variable fragment, that binds to CD3 of a T-cell antigen receptor and an antibody, fragment thereof, or single chain variable fragment that binds to PDL1 on a cancerous tumor cell to counteract immune tolerance of cancer cells (abstract).
WO’453 teaches a method comprising providing at least one recombinant vector comprising nucleotide sequences that encode an anti-CD3 antibody and an anti-PDL1 antibody comprising the nucleotide sequences of SEQ ID NOs: 1 to 4; and administering a vector comprising the nucleotides to a subject under conditions such that the nucleotide sequences are expressed at a level which produces a therapeutically effective amount of the encoded bispecific fusion protein, wherein the expressed amino acid residues include SEQ ID NOs: 5 and 6 for the light and heavy chains of the anti-PDL1 antibody, respectively (page 4, [0015]).
WO’453 SEQ ID NOs: 1 and 2 are identical to instant SEQ ID NOs: 13 and 14, respectively, as shown in the alignments below:
WO’453, SEQ ID NO: 1 aligned with instant SEQ ID NO: 13
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WO’453, SEQ ID NO: 2 aligned with instant SEQ ID NO: 14
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Additionally, the proteins encoded by the nucleic acids, WO’453, SEQ ID NOs: 5 and 6, are identical to instant SEQ ID NOs: 6 and 7, respectively, as shown in the alignments below:
WO’453, SEQ ID NO: 5 aligned with instant SEQ ID NO: 6
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WO’453, SEQ ID NO: 6 aligned with instant SEQ ID NO: 7
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WO’453 further teaches a method of preparing an anti-CD3/anti-PDL1 bispecific fusion protein comprising transfecting a host cell with a polynucleotide that encodes the protein where the nucleotide sequence is SEQ ID NO: 9 and maintaining the transformed host cell under biological conditions sufficient for expression of the bispecific fusion protein having an amino acid sequence of SEQ ID NO: 10 (page 28, claim 16). WO’453, SEQ ID NO: 10, comprises an amino acid sequence that includes an amino acid sequence that is identical to instant SEQ ID NO: 6 linked to an amino acid sequence identical to instant SEQ ID NO: 7 via a (G4S)3 linker, as shown in the alignment of WO’453, SEQ ID NO: 10 with instant SEQ ID NOs: 6 and 7 below:
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The fusion of the sequences using a linker meets the instant claim 4 limitation of “operatively linked” based on the definition in the instant specification, page 14, [0058], which states that “By operably linked” to one another, it is meant that there is a direct or indirect covalent linking between the peptides comprising the fusion protein. Thus, two domains that are operably linked may be directly covalently coupled to one another. Conversely, the two operably linked domains may be connected by mutual covalent linking to an intervening moiety (e.g., and flanking sequence). Two domains may be considered operably linked if, for example, they are separated by the third domain, with or without one or more intervening flanking sequences.”
WO’453 further teaches that the polypeptides are produced by recombinant DNA techniques by synthesizing DNA encoding the desired polypeptide. Once coding sequences for the desired polypeptides have been synthesized or isolated, they can be cloned into the vector for expression (page 17, [0064]), indicating that the polynucleotide encoding SEQ ID NO: 10, which is disclosed as SEQ ID NO: 9, is isolated.
WO’453 further teaches a method of treating cancer and/or killing cancerous tumor cells comprising administering to a subject an anti-CD3/anti-PDL1 bispecific fusion protein wherein the binding to the CD3 receptor on a T-cell activates CD4+ and CD8+ T cells that are cytotoxic for a PDL1+ tumor and thereby inducing increased cell death of the PDL1+ tumor cells (page 27, claim 9). WO’453 also teaches that the cancer is a PDL1+ human melanoma, breast cancer, AML, GBM, CML, or NSCLC (page 28, claim 15). As WO’453 teaches the fusion protein of SEQ ID NO: 10 and a sufficiently small number of cancers for treatment with the fusion protein, an ordinarily skilled artisan would have reasonably envisaged the treatment of each of the cancers with the fusion protein. See MPEP 2131.02 III.
Thus, WO’453 anticipates instant claims 1-4, 17, 19, and 22.
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, 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 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/106453 A1 (Ostrand-Rosenberg, S. and D.L. Carter) 22 June 2017 in view of Hudson, P.J. and A.A. Kortt (1999) High avidity scFv multimers; diabodies and triabodies Journal of Immunological methods 231; 177-189.
The teachings of WO’453 are as discussed above.
As discussed above, WO’453 teaches a fusion protein comprising instant SEQ ID NO: 6 operably linked to instant SEQ ID NO: 7 with a linker forming an scFv. WO’453 further teaches that the antibody fragments can include a portion of the intact antibody, for example, Fab, Fab’, F(ab’)2, and Fv fragments; Fc fragments or Fc-fusion products; diabodies; linear antibodies; single chain antibody molecules; and multispecific antibodies formed from antibody fragments (page 15, [0058]).
WO’453; however, does not disclose that the sequence are directly linked as recited in the claims 5-6 or that the orientation is SEQ ID NO: 7 – 6.
Hudson presents a review describing how the careful choice in linker length between V-domains in antibodies creates new types of Fv molecules with size, flexibility, and valency suited to in vivo imaging and therapy. ScFvs are predominantly monomeric when the VH and VL domains are joined by peptide linkers of at least 12 residues. An scFv molecule with a linker of 3 to 12 residues cannot fold into a functional Fv domain and instead associates with a second scFv molecule to form a bivalent dimer (diabody, ~60 kDa). Reducing the linker length below three residues can force scFv association into timers (triabodies, ~90 kDa) or tetramers (~120 kDa) depending on linker length, composition, and V domain orientation. The increased binding valency in these scFv multimers results in high avidity (abstract). Hudson provides a schematic of the domains in Fig. 1 on page 178.
Hudson further teaches that, when the linker is removed completely in VH-VL orientation so that the C-terminal residue of the VH domain is linked directly to the N-terminal residue of the VL domain, three scFv molecules associate to form a trimer, termed a triabody (page 180, left column, paragraph 1). Hudson also teaches the formation of triabodies when VL-VH domains were joined directly (page 180, right column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to form the anti-PD-L1 binding domain disclosed by WO’453 by directly linking the C-terminus of VL and the N-terminus of the VH or, alternatively, by directly linking the C-terminus of the VH and the N-terminus of the VL based on the teachings of Hudson. An ordinarily skilled artisan would have been motivated to directly link the VH and VL domains, in either orientation, as Hudson teaches that doing so can result in the formation of triabodies and teaches that such scFv multimers increases biding valency resulting in high avidity. An ordinarily skilled artisan would have had a reasonable expectation of success as Hudson teaches direct linkage as an alternative to scFvs formed with linkers. Additionally, WO’453 teaches that the antibody fragments can be in various forms including diabodies, which Hudson teaches as an alternative to triabodies formed with no linker.
Claims 1-4, 8-11, 15-17, and 19-25 are rejected under 35 U.S.C. 103 as being unpatentable over US 11,098,100 B2 (Vallera, D.A. and J.S. Miller) 24 Aug 2021 in view of WO 2017/106453 A1 (Ostrand-Rosenberg, S. and D.L. Carter) 22 June 2017 and WO 2019/035939 A1 (Chang, G.P., et al) 21 Feb 2019.
US’100 teaches the design, construction, and use of trispecific killer engager (TriKE) molecules (col. 1, lines 32-33).
US’100 teaches that the engineered compounds that engage NK cells and methods of using the compounds. Generally, the compound includes an NK engaging domain, a targeting domain that selectively binds to a target cell, and an NK activating domain operably linking the NK engaging domain and the targeting domain (abstract).
US’100 teaches that the NK activating domain can include at least a portion of a cytokine, the NK engaging domain can include a moiety that selectively binds to an NK cell, and the targeting domain can be an antibody or a fragment thereof and can target a cell including a tumor cell (col. 1, lines 40-53).
US’100 exemplifies a TriKE as shown in Fig. 1A (right image), which is duplicated below for convenience:
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US’100 teaches a compound comprising:
an NK engaging domain comprising amino acid residues 1-240 of SEQ ID NO: 1 or amino acid residues 19-140 of SEQ ID NO: 14;
an NK activating domain comprising the amino acid of SEQ ID NO: 15, or the amino acid of SEQ ID NO: 15 comprising an N72D or N72A amino acid substitution;
a first linker linking the NK engaging domain to the NK activating domain;
a targeting domain that selectively binds to a target antigen; and
a second linker linking the NK activating domain to the targeting domain (col. 93, claim 1).
The NK engaging domain of amino acid residues 1-240 of US’100, SEQ ID NO: 1 are identical to instant SEQ ID NO: 23 as shown in the alignment below:
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Additionally, the NK engaging domain of amino acid residues 19-140 of US’100, SEQ ID NO: 14 is identical to instant SEQ ID NO: 2, as shown in the ABSS alignment below:
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The NK activating domain of US’100, SEQ ID NO: 15 is identical to instant SEQ ID NO: 4, as shown in the alignment below:
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Additionally, as discussed above, US’100 also teaches N72D or N72A substitutions in the amino acid sequence of SEQ ID NO: 15, which would render sequences that are identical to instant SEQ ID NOs: 21 and 22, respectively.
US’100 further teaches that the first linker comprises SEQ ID NO: 3 and the second linker comprises SEQ ID NO: 4 (col. 96, claim 17).
US’100, SEQ ID NOs: 3 and 4 are identical to instant SEQ ID NOs: 16 and 17, as shown in the alignments below:
US’100, SEQ ID NO: 3 aligned with instant SEQ ID NO: 16
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US’100, SEQ ID NO: 4 aligned with instant SEQ ID NO: 17
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Alternatively, US’100 teaches that the first and second linkers can comprise those used in SEQ ID NO: 14 (col. 96, claims 17-18). US’100, SEQ ID NO: 14 comprises linkers that are identical to instant SEQ ID NOs: 3 and 5, respectively, as shown in the alignments below:
US’100, SEQ ID NO: 14 aligned with instant SEQ ID NO: 3
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US’100, SEQ ID NO: 14 aligned with instant SEQ ID NO: 3
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US’100 further teaches that the targeting domain comprises a moiety that selectively binds to a tumor cell including an antibody or an antigen binding fragment thereof, including an scFv (col. 94, claims 6-8).
US’100 teaches methods of killing a target cell in a subject comprising administering to the subject the TriKE molecule in an amount effective to induce NK-mediated killing of the target cells. “Treat” or variations thereof, refer to reducing, limiting progression, ameliorating, or resolving, to any extent, the symptoms or signs related to a condition (col. 23, line 62 – col. 24, line 8). US’100 teaches that the TriKE molecule can have a targeting domain that binds an appropriate target cell population and that the target cell can include a tumor cell so that the method can involve treating cancer associated with the tumor cells. Thus, in some embodiments, the method can include ameliorating at least one symptom or clinical sign of the tumor (col. 26, lines 12-19).
US’100 teaches that the tumors that can be treated include tumors associated with prostate cancer, lung cancer, colon cancer, rectum cancer, urinary bladder cancer, melanoma, kidney cancer, renal cancer, oral cavity cancer, pharynx cancer, pancreas cancer, uterine cancer, thyroid cancer, skin cancer, head and neck cancer, cervical cancer, ovarian cancer, and/or hematopoietic cancer (col. 26, lines 20-30).
The TriKE disclosed by US’100 differs from the instant claims in that it does not comprise instant SEQ ID NOs: 6 and 7.
The teachings of WO’453 are as discussed above.
As discussed in detail above, WO’453 teaches an anti-PD-L1 VH and VL that are identical to instant SEQ ID NOs: 6 and 7 and provides a sequence in which they are operably linked in the form of an scFv in the 6-7 orientation. WO’453 also teaches the inclusion of the VH and VL and scFv in a bispecific T cell engager fusion polypeptide which binds to CD3 of a T cell receptor and PDL1 on a cancerous tumor or cell to counteract immune tolerance of cancer cells (abstract).
WO’939 teaches multi-specific binding proteins that bind NKG2D, CD16, and a tumor-associated antigen selected from EGFR, HLA-E, CCR4, and PD-L1 (abstract).
WO’939 teaches that cancer immunotherapies are desirable because they are highly specific and can facilitate destruction of cancer cells using the patient’s own immune system. Fusion proteins, such as bi-specific T cell engagers are cancer immunotherapies described in the literature that bind to tumor cells and T-cells to facilitate destruction of tumor cells (page 1, [0005]).
Natural killer (NK) cells are a component of the innate immune system and make up approximately 15% of circulating lymphocytes. NK cells infiltrate virtually all tissues and were originally characterized by their ability to kill tumor cells effectively without the need for prior sensitization. Activated NK cells kill target cells by means similar to cytotoxic T cells and also secrete inflammatory cytokines and chemokines that promote recruitment of other lymphocytes to the target tissue (page 2, [0006]).
WO’939 further teaches that PD-L1 plays an important role in maintaining immune homeostasis. It binds to PD-1 receptor on T cells, and down regulates cytotoxic T cell, thereby protecting normal cells from collateral damage. Development and progression of tumor are accompanied by the formation of special tumor immune microenvironments. Tumors can escape the immune surveillance and disrupt immune checkpoint of host by overexpressing PD-L1. When PD-L1 binds to PD-1, an inhibitory signal is transmitted into the T cell, which reduces cytokine production and suppresses T cell proliferation. Tumor cells exploit this immune checkpoint pathway as a mechanism to evade detection and inhibit immune response. PD-L1 is overexpressed in various types of cancer, especially in lymphoma, leukemia, multiple myeloma, head and neck cancer, bladder cancer, cervical cancer, lung cancer, renal cancer, melanoma, colorectal cancer, ovarian cancer, glioblastoma, sarcomas, and gastric cancer (page 3, [0012]).
WO’939 teaches that binding of the multi-specific binding proteins to PD-L1 expressing cells brings the cancer cells into proximity with the NK cells, which facilitates direct and indirect destruction of the cancer cells with the NK cell (page 28, [0140]).
WO’939 further teaches methods of treating cancer comprising administering a therapeutically effective amount of the multi-specific binding proteins (page 18, [0071]). Additionally, WO’939 teaches that the multi-specific binding proteins can be used in combination with additional agents to treat the cancer (page 68, [0228]). A class of agents that may be used as part of the combination therapy in treating cancer is immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include agents that inhibit one or more of CTLA4, PD1, PDL1, LAG3, B7-H3, B7-H4, and TIM3. The CTLA4 inhibitor ipilimumab has been approved by the FDA for the treatment of melanoma (page 69, [0230]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the TriKE fusion proteins taught by US’100 by substituting the targeting domain that selectively binds to a target antigen with the anti-PD-L1 antibody VH and VL of SEQ ID NOs: 6 and 7 disclosed by WO’453 which is further supported by WO’939. It would have been obvious to substitute the target antigen domain with the anti-PD-L1 antibody disclosed by WO’453 as both WO’453 and WO’939 demonstrate the known expression of PD-L1 on tumor cells and use anti-PD-L1 antibodies as a means to target tumor cells in fusion proteins. Additionally, WO’939 teaches that PD-L1 is overexpressed on various types of cancer and that, by targeting PD-L1 with an fusion protein that also targets NK cells, including by targeting CD16, the PD-L1 expressing cells can be brought into proximity with the NK cells facilitating direct and indirect destruction of the cancer cells with the NK cell. An ordinarily skilled artisan would have had a reasonable expectation of success as all of US’100, WO’453, and WO’939 are teaching fusion proteins designed to bring cells of the immune system into proximity with cancer cells. Additionally, the references teach overlapping cancers that can be treated including hematopoietic cancers, head and neck cancer, bladder cancer, cervical cancer, lung cancer, renal cancer, melanoma, colorectal cancer, and ovarian cancer demonstrating further nexus among the art.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over US 11,098,100 B2 (Vallera, D.A. and J.S. Miller) 24 Aug 2021 in view of WO 2017/106453 A1 (Ostrand-Rosenberg, S. and D.L. Carter) 22 June 2017, WO 2019/035939 A1 (Chang, G.P., et al) 21 Feb 2019, and Hudson, P.J. and A.A. Kortt (1999) High avidity scFv multimers; diabodies and triabodies Journal of Immunological methods 231; 177-189.
The teachings of US’100 are as discussed above.
As discussed in detail above, US’100 exemplifies a TriKE as shown in Fig. 1A (right image) which comprises an anti-CD16 antibody linked to IL-15 linked to an anti-CD33 tumor targeting antibody.
Specifically, US’100 exemplifies the construction of EF91 (Ilama anti-human IL16)-IL-15-anti-CD33 in example 3 (col. 34) which has an amino acid sequence of SEQ ID NO: 14 (col. 34, lines 55-59).
US’100, SEQ ID NO: 14 comprises amino acids 1-276 of instant SEQ ID NO: 1, as shown in the alignment below.
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As shown in the alignment above, US’100, SEQ ID NO: 14 differs from instantly claimed SEQ ID NO: 1 in the sequence of the targeting domain that selectively binds to a target antigen.
US’100 does not disclose an antigen binding domain comprising instant SEQ ID NO: 14, amino acids 277 – 505.
The teachings of WO’453, WO’939, and Hudson are as discussed in detail above.
As discussed in detail above, WO’453 teaches the VL and VH domains of an anti-PD-L1 antibody comprising SEQ ID NOs: 5 and 6, respectively (page 4, [0015]) and Hudson teaches high avidity scFv multimers in which VL and VH antibody domains are directly linked so that the C-terminal residue of the VL domain is directly linked to the N-terminal of the VH domain (page 180, left column, paragraph 1).
Directly linking the VL and VH domains of WO’453 directly, as taught by Hudson, provides a sequence that is identical to instant SEQ ID NO: 1, amino acids 277-505, as shown in the alignment below:
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Substituting the anti-PD-L1 binding domain above in place of the anti-CD33 antibody binding domain in the fusion protein of US’100 results in a sequence that is identical to instant SEQ ID NO: 1 as shown in the alignment below:
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the TriKE fusion proteins taught by US’100 by substituting the targeting domain that selectively binds to a target antigen with the anti-PD-L1 antibody VH and VL of SEQ ID NOs: 6 and 7 disclosed by WO’453 which is further supported by WO’939. It would have further been obvious to form the anti-PD-L1 binding domain disclosed by WO’453 by directly linking the C-terminus of VL and the N-terminus of the VH or, alternatively, by directly linking the C-terminus of the VH and the N-terminus of the VL based on the teachings of Hudson.
It would have been obvious to substitute the target antigen domain with the anti-PD-L1 antibody disclosed by WO’453 as both WO’453 and WO’939 demonstrate the known expression of PD-L1 on tumor cells and use anti-PD-L1 antibodies as a means to target tumor cells in fusion proteins. Additionally, WO’939 teaches that PD-L1 is overexpressed on various types of cancer and that, by targeting PD-L1 with an fusion protein that also targets NK cells, including by targeting CD16, the PD-L1 expressing cells can be brought into proximity with the NK cells facilitating direct and indirect destruction of the cancer cells with the NK cell. An ordinarily skilled artisan would have had a reasonable expectation of success as all of US’100, WO’453, and WO’939 are teaching fusion proteins designed to bring cells of the immune system into proximity with cancer cells. Additionally, the references teach overlapping cancers that can be treated including hematopoietic cancers, head and neck cancer, bladder cancer, cervical cancer, lung cancer, renal cancer, melanoma, colorectal cancer, and ovarian cancer demonstrating further nexus among the art.
An ordinarily skilled artisan would have been motivated to directly link the VH and VL domains, in either orientation, as Hudson teaches that doing so can result in the formation of triabodies and teaches that such scFv multimers increases biding valency resulting in high avidity. An ordinarily skilled artisan would have had a reasonable expectation of success as Hudson teaches direct linkage as an alternative to scFvs formed with linkers. Additionally, WO’453 teaches that the antibody fragments can be in various forms including diabodies, which Hudson teaches as an alternative to triabodies formed with no linker.
Claims 12 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over US 11,098,100 B2 (Vallera, D.A. and J.S. Miller) 24 Aug 2021 in view of WO 2017/106453 A1 (Ostrand-Rosenberg, S. and D.L. Carter) 22 June 2017 and WO 2019/035939 A1 (Chang, G.P., et al) 21 Feb 2019 as applied to claims 8 and 23 above and in further view of US 2017/0218078 A1 (Raum, T., et al) 3 Aug 2017.
The combination of US’100, WO’453, and WO’939 teach the fusion proteins of claim 8 and 23 as discussed in detail above.
The combination of applied references, however, does not disclose that the furoin protein further comprises a half-life extending (HLE) molecule.
US’078 teaches that bispecific molecules, such as BiTE antibody constructs, are recombinant proteins made from two flexibly linked antibody derived binding domains. One of the binding domains of a BiTE antibody is specific for a selected tumor associated surface antigen on target cells while the second is specific for a subunit of the T cell receptor (page 1, [0001]). Such antibody constructs, however, are likely to suffer from rapid clearance from the body; thus, while they are able to reach most parts of the body rapidly, and are quick to produce and easier to handle, their in vivo applications may be limited by their brief persistence in vivo (page 1, [0002]).
An increase in half-life is generally useful in in vivo applications of immunoglobulins, especially antibodies and most especially antibody fragments of small size. Approaches described in the art to achieve such effect comprise the fusion of the small bispecific antibody constructs to larger proteins that, preferably, do not interfere with the therapeutic effect of the antibody construct. Examples of such include F-molecules or, alternatively HSA (page 1, [0003]). US’078 teaches that half-life extending (HLE) formats described in the art include hetero Fc (also designated hetFc, heterodimeric Fc, hFc). US’078; however, teaches that there are some limitations to these HLEs and provides bispecific antibody constructs of a specific Fc modality characterized by a first and second binding domain and an additional domain that is the specific Fc modality (page 1, [0004]). US’078 teaches that the antibody constructs disclosed also have superior affinity characteristics in comparison to other HLE formats. Such a superior affinity, in consequence, suggests a prolonged half-life in vivo. The longer half-life of the antibody constructs may also reduce duration and frequency of administration, which typically contributes to improved patient compliance (pages 8-9, [0062]). US’078 also teaches that the HLE can be a single-chain-Fc (scFc) or hetero-Fc fused at the C terminus of the BiTE constructs (page 32, [0354]).
US’078 teaches that the term “bispecific antibody construct” of the invention also encompasses multispecific antibody constructs such as trispecific constructs, the latter ones comprising three binding domains, or constructs having more than three specificities (page 3, [0024]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the fusion proteins disclosed by the combination of US’100, WO’453, and WO’939 by further including a half-life extension modality, such as an Fc or a scFc, as disclosed by US’078. An ordinarily skilled artisan would have been motivated to further include an HLE modality in order to increase the half-life of the fusion proteins in vivo which US’078 teaches can result in superior affinity characteristics while also reducing the duration and frequency of required administration. An ordinarily skilled artisan would have had a reasonable expectation of success as US’078 is teaching methods of increasing the half-life of fusion proteins, including trispecific constructs, and the combination of US’100, WO’453, and WO’939 teach a trispecific fusion protein (TriKE).
Claims 4, and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over US 11,098,100 B2 (Vallera, D.A. and J.S. Miller) 24 Aug 2021 in view of WO 2017/106453 A1 (Ostrand-Rosenberg, S. and D.L. Carter) 22 June 2017, WO 2019/035939 A1 (Chang, G.P., et al) 21 Feb 2019, Hudson, P.J. and A.A. Kortt (1999) High avidity scFv multimers; diabodies and triabodies Journal of Immunological methods 231; 177-189, US 7,169,894 B2 (Martin, M.T.) 30 January 2007, and Gould, N., et al (2014) Computational tools and algorithms for designing and customized synthetic genes Frontiers in Bioengineering and Biotechnology 2(41); 1-14.
The teachings of US’100 are as discussed in detail above.
As discussed in detail above, US’100 exemplifies the anti-human CD16-IL-15-CD33 TriKE of SEQ ID NO: 14 and teaches the production of a polynucleotide encoding the construct, but does not disclose the nucleic acid sequence (col. 34-35; example 3).
US’100; however, does not disclose the fusion protein of claim 4, or the nucleic acids of instant claims 17 and 18.
The teachings of WO’453, WO’939, and Hudson are as discussed in detail above.
WO’453 teaches an anti-PD-L1 antibody VL and VH with amino acid sequences that are identical to instant SEQ ID NO: 6 and 7 and also teaches a fusion protein in which the sequences are operably linked together. As discussed above, WO’453 also teaches nucleic acids encoding the VL and VH sequences of the antibody. It is noted that, together, the VL and VH nucleotide sequences disclosed by WO’453 are identical to instant SEQ ID NO: 8, amino acids 829-1515.
As discussed in detail above in the rejection of instant claim 7, the combination of US’100, WO’453, WO’939, and Hudson teach an amino acid sequence that is identical to instant SEQ ID NO: 1. While the references do not disclose the nucleotides recited in instant claim 18, the combination of references do disclose the amino acid sequence that is encoded by at least instant SEQ ID NO: 8, which is instant SEQ ID NO: 1.
US’894 discusses processes through which polynucleotides are synthesized from a specific peptide or protein that they encode both through traditional techniques and via processes where sequence analysis of the peptide is not required (abstract; column 3, lines 5-17). US’894 teaches that reverse translation is the step of informational coupling of individual amino acids to their corresponding codons. Natural codons are trinucleotides and the three-nucleotide sequences of a codon specifies, or encodes, a specific amino acid (column 9, lines 29-33; Figure 1). There are 20 genetic code-encoded amino acids with 64 amino acid-encoding codons in the natural genetic code (column 18, lines 4-7; Figure 1). US’894 teaches that synthesis of an encoding polynucleotide, including RNA or DNA, that encodes a specific peptide or protein conventionally involves purifying a peptide or protein and sequencing it using an automated amino acid sequencing machine. Following sequencing, the identity and order of the amino acids are read and an oligonucleotide is synthesized using a second instrument, an oligonucleotide synthesizer. From the prepared oligo, the full-length polynucleotide can be cloned and the protein can be produced (column 3, lines 5-17).
Gould teaches that advances in DNA synthesis have enabled the construction of artificial genes and freedom in de novo design of synthetic constructs. To aid this goal, a large number of software tools of variable sophistication have been implemented enabling the design of synthetic genes for sequence optimization based on rationally designed properties. Gould teaches that years recent to the publication had seen the emergence of sequence design tools that aim to evolve sequences toward combinations of objectives. Gould provides a review of the approaches that different tools have adopted to redesign genes and optimize desired coding features and discusses their strengths and limitations (abstract). Gould provides a review of the most important objectives in synthetic gene design towards optimized expression as well as a review of 11 gene design tools that were available at the time of publication that incorporate the aforementioned objectives (page 1, right column, paragraph 3; page 4, table 1). The gene design tools disclosed can be used to translate and optimize DNA sequences without altering the chain of amino acids (page 4, left column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use reverse translation techniques known in the art, such as the methods of US’894 and/or the computational tools disclosed by Gould, to reverse translate the amino acid sequences disclosed by the combination of US’100, WO’453, WO’939, and Hudson into a nucleic acid sequence for encoding the fusion protein. This conclusion of obviousness is further supported by KSR(E) obvious to try. In this case, the combination of US’100, WO’453, WO’939, and Hudson teach a fusion protein with an amino acid sequence that is identical to that of the instantly disclosed invention and also demonstrate the use of isolated nucleic acids encoding the amino acid sequences. US’894 teaches that there are 20 genetically encoded amino acids with 64 amino acid-encoding codons and both US’894 and Gould demonstrate that reverse translation was commonly practiced in the art of protein and gene synthesis. Therefore, an ordinarily skilled artisan would have been able to pursue the known potential solutions with a reasonable expectation that the resulting nucleic acid would encode the amino acid sequence that it was reverse translated from, specifically that disclosed by the combination of US’100, WO’453, WO’939, and Hudson.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 4-24 are rejected on the ground of provisional nonstatutory double patenting as being unpatentable over claims 4-27 of copending application 18/690,991 in view of WO 2017/106453 A1 (Ostrand-Rosenberg, S. and D.L. Carter) 22 June 2017, US 11,098,100 B2 (Vallera, D.A. and J.S. Miller) 24 Aug 2021, and WO 2019/035939 A1 (Chang, G.P., et al) 21 Feb 2019.
App’991 claims a fusion protein comprising SEQ ID NO: 1 and sequences having 90% or greater identity to SEQ ID NO: 1 (claim 7). App’997 further claims a fusion protein comprising SEQ ID NOs: 2 or 19; 4, 17, or 18, 6 and 7 or 7 and 6 (claim 8). App’991 claims that SEQ ID NOs: 2 or 19 and 4, 17, or 18 are linked by SEQ ID NO: 4 or 15 (claim 9) and that SEQ ID NOs: 4, 17, or 18, and 6 or 7 are linked by SEQ ID NO: 5 or 16 (claim 10). App’991 claims that SEQ ID NOs: 6 and 7 are in operable linkage in either orientation. App’991 further claims that the fusion protein further comprises a half-life extending (HLE) molecule and that the HLE molecule is a Fc or a scFc antibody fragment comprising any one of SEQ ID NOs: 21-25 (claim 13). App’991 claims that SEQ ID NO: 4 has a N72 mutation (claim 14) including N72A or N72D (claim 15). App’991 claims that the fusion protein is set forth in SEQ ID NO: 17 or 18, is encoded by an isolated nucleic acid sequence, and that the isolated nucleic acid sequence is SEQ ID NO: 8 (claims 16-17). App’991 claims a method of treating cancer in a subject comprising administering to the subject a fusion protein and claims that the cancer includes NSCLC, pancreatic cancer, colorectal cancer, and breast cancer (claim 20). App’991 claims a fusion protein comprising SEQ ID NO: 19, SEQ ID NO: 17 or 18, and SEQ ID NO: 6 and 7 in either orientation (claim 21), where SEQ ID NO: 19 is operably linked to SEQ ID NO: 17 or 18 by a inker of SEQ ID NO: 3 or 15 (claim 22) and SEQ ID NO: 17 or 18 is operably linked to SEQ ID NO: 6 and 7, in either orientation, by a linker of SEQ ID NO: 5 or 16 (claim 23). The fusion protein is further claimed to have a HLE molecule comprising any one of SEQ ID NO: 21-25 (claim 25). App’991 further claims a pharmaceutical composition comprising SEQ ID NO: 1 or a sequence with 90% identity thereof, and a method of treating cancer comprising administering the pharmaceutical composition (claims 26-27).
The sequences claimed in App’991 are the same as those of the instant claims with the exception of instant SEQ ID NOs: 6 and 7 and the nucleic acid encoding these amino acid sequences.
The teachings of US’100, WO’453, and WO’939 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the sequences claimed in App’991 by substituting App’991, SEQ ID NO: 6 and 7 with the anti-PD-L1 VL and VH amino acid/nucleic acid sequences disclosed by WO’453 based on the teachings of US’100 and WO’939. It would have been obvious to substitute the sequences in App’991 with those taught by WO’453 as US’100 establishes that the sequences claimed in App’991 are fusion proteins comprising an anti-CD16 antibody operably linked to IL-15 (and variants thereof) which are operably linked to an target binding domain. US’100 also exemplifies such a fusion protein in SEQ ID NO: 14 which has sequences that are identical to those of App’991 and the instant claims with the exception of the binding domain. Both WO’453 and WO’939 demonstrate the known expression of PD-L1 on tumor cells and use anti-PD-L1 antibodies as a means to target tumor cells in fusion proteins. Additionally, WO’939 teaches that PD-L1 is overexpressed on various types of cancer and that, by targeting PD-L1 with an fusion protein that also targets NK cells, including by targeting CD16, the PD-L1 expressing cells can be brought into proximity with the NK cells facilitating direct and indirect destruction of the cancer cells with the NK cell. An ordinarily skilled artisan would have had a reasonable expectation of success as all of App’991, US’100, WO’453, and WO’939 are drawn to fusion proteins designed to bring cells of the immune system into proximity with cancer cells.
Allowable Subject Matter
Claims 13 and 27 are rejected above on the ground of provisional nonstatutory double patenting over copending application 18/690,991 and are objected to as being dependent upon a rejected base claim. The claims would be allowable if the nonstatutory double patenting rejection is overcome and if the claims were rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: claims 13 and 27 are drawn to HLE molecules comprising an Fc or a scFc antibody fragment comprising any one of SEQ ID NOs: 25-29. In searches of the prior art, no sequences matching the instantly claimed sequences were identified. The following is considered to be the closest prior art.
US 2017/0029512 A1 (Raum, T., et al) 02 Feb 2017
US’512 teaches bispecific antibody constructs that bind human EGFRVIII on a target cell and human CD3 on the surface of a T cell as well as polynucleotides encoding the constructs, vectors comprising the polynucleotides, and host cells transformed or transfected with the vector (abstract). US’512 further teaches that the constructs further have fully functional Fc constant domains as a means to enhance serum half-life (page 13, [0120]). Examples for means to extend serum half-life of the antibody constructs include peptides, proteins, or domains of proteins that are fused or otherwise attached to the antibody constructs. Such half-life extending domains includes peptides binding to the neonatal Fc receptor. US’512 also teaches that the half-life extension domain can include the fusion of constant regions of immunoglobulins (Fc domains) and variants thereof. Such variants of Fc domains may be optimized/modified in order to allow the desired pairing of dimers or multimers, to abolish Fc receptor binding or for other reasons (page 13, [0121]). US’512 teaches a hetero-Fc binder Fc comprising SEQ ID NO: 144 (page 44), which has the following alignment with instant SEQ ID NO: 27:
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As shown in the alignment above, the sequence disclosed by US’512 comprises the sequence “VVV” while the instant sequence, in the same location, comprises “WV”.
In searches of the prior art, no teachings or suggestions were identified that would lead an ordinarily skilled artisan to substitute “VVV” in the sequence disclosed by US’512 with “WV” to arrive at the instantly claimed sequence with a reasonable expectation of success.
As such, claims 13 and 27 were found to be novel and non-obvious.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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