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 .
Claims Status
The remarks filed 01/27/2026 are acknowledged.
Claims 1-5, 9-10, 14-15, 17, 25-27, 33, 35, 38-39, 41, and 44-45 are pending.
Claims 3-5, 9-10, 14-15, 17, 25-27, 33, 35, 38-39, 41, and 44-45 are amended.
Claims 6-8, 11-13, 16, 18-24, 28-32, 34, 36-37, 40, and 42-43 are cancelled.
Applicant's election with traverse of Group I, claims 1-5, 9-10, 14-15, 17, 25-27, 33, 35, and 38-39 in the reply filed on 01/27/2026 is acknowledged. Applicant’s election of the following species with traverse in the response filed on 01/27/2026 is acknowledged: Formula Ia, as recited in instant claims 4 and 14, for where the anti-TGF-B antibody or element is connected to the anti-PD-L1 antibody. Upon further consideration, the election of species requirement is withdrawn.
The traversal is on the ground(s) that the search and examination of all currently pending claims would not pose an undue burden on the Examiner, and Applicant cites MPEP 803. This is not found persuasive because the claims were restricted based on 371 practice and burden of search is not a consideration for the propriety of the holding of Lack of Unity. The requirement is still deemed proper and is therefore made FINAL.
Claims 41, 44, and 45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and/or species there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 01/27/2026.
Therefore, claims 1-5, 9-10, 14-15, 17, 25-27, 33, 35, and 38-39 are under examination.
Priority
The instant application is a 371 of PCT/CN2021/134824 and claims priority to People’s Republic of China Application #CN202011401649.6. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) and receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Although the certified copy of the foreign priority document was received, the Examiner is unable to determine whether or not the Chinese foreign priority document discloses what is presently claimed because the document is in Chinese. Therefore, priority is given with the effective filing date of 12/01/2021, which is the PCT filing date.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/01/2023 is in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Drawings
The drawings are objected to because Figures 1-3, 10, and 11 comprise multiple panels. 37 CFR 1.84(u) states that the different views must be numbered in consecutive Arabic numerals and that "partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter". Each panel should be separately numbered. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 recites “PD-L1” and “TGF-β”. The first time an acronym is used, it must be accompanied by the definition of the abbreviation. Appropriate correction 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 1-5, 9-10, 14-15, 17, 25-27, 33, 35, and 38-39 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 1 recites “A bifunctional antibody, wherein, said bifunctional antibody comprises: (a) an anti-PD-L1 antibody or element; and (b) an anti-TGF-β antibody or element connected to said anti-PD-L1 antibody or element.” First, it is unclear what is meant by “element” and there is no limiting definition of “element” in the instant specification. The claim does not require that the “element” be of the anti-PD-L1 antibody or of the anti-TGF-β antibody, and therefore the “element” could be anything that is anti-PD-L1 or anti-TGF-β, or a fragment of the antibodies. Second, the art accepted definition of a bifunctional (i.e. bispecific) antibody is an antibody that can bind to two different antigens at the same time, wherein each arm binds to a different antigen. Thus, if option (a) of claim 1 is an “element” and option (b) of claim 1 is an “element” this would not be a bifunctional antibody. The claim reads on any “element” being bound to any other “element”, and therefore, the scope of this claim is indefinite.
Claims 2-5, 9-10, 14-15, 17, 25-27, 33, 35, and 38-39, which depend from claim 1, are therefore indefinite for the same reasons set forth above.
The Examiner notes that claims 9-10 and 15 do set forth a structure for the anti-TGF-β “element” and claims 3-5, 14, 25-27, 33, and 35 require that the bifunctional antibody comprise an anti-PD-L1 antibody and not an anti-PD-L1 “element”. However, taken in total, these claims do not remedy the indefiniteness of both the anti-TGF-β element and the anti-PD-L1 element.
Claim 3 recites the limitations “said anti-TGF-β antibody or element is connected to a region of said anti-PDL1 antibody selected from the following group: a heavy chain variable region, a heavy chain constant region, a light chain variable region, or a combination thereof”, claim 4 recites that “said anti-TGF- β antibody or element is connected to an initial terminal of the heavy chain variable region of said anti-PD-L1 antibody”, claim 5 recites that “said anti-TGF-B antibody or element is connected to a terminal end of the heavy chain constant region of the anti-PD-L1 antibody”, claims 25 and 27 recite “the heavy chain variable region (VH) of said anti-PD-L1 antibody”, and claims 26 and 27 recite “the light chain variable region (VL) of said anti-PD-L1 antibody”. There is insufficient antecedent basis for the limitations in these claims. Claim 1, upon which claims 3, 4, 5, 25, 26, and 27 depend, does not recite a heavy chain variable region, a heavy chain constant region, or a light chain variable region. While it reasonably appears that that the antibody must have at least a heavy chain variable region, a heavy chain constant region, and a light chain variable region [see Figure 2 of the instant specification], the antibody does not necessarily comprise more than the heavy chain variable region (i.e. a VHH) or a heavy chain variable region and a light chain variable region (i.e. a scFv), and would not comprise any constant domains.
Claim 9 recites the limitation “wherein said element comprises an extracellular region of a ligand, a receptor, or a protein.” Claim 9 depends from claim 1 where there are two “elements” recited in claim 1. It is unclear which element claim 9 is referring to. Therefore, the scope of this claim is indefinite.
For purposes of examination, the Examiner is interpreting claim 9 as referring to the element of (b) since the invention seems to be drawn to a bifunctional fusion protein comprising an anti-PD-L1 antibody and a TGF-βRII extracellular region [see paragraphs 129, 135, and Figure 2 of the instant specification].
Claim 10 recites “wherein the number of said anti-TGF-β element is 1 to 4.” It is unclear if this limitation is referring to the TGF-β receptor being TGF-βI, TGF-βII, TGF-βIII, or TGF-βIV, or if this is referring to the number of units of TGF-β receptor attached to the anti-PDL1 antibody or element. Therefore, the scope of this claim is indefinite.
Claim 17 recites “said adapter element”. There is insufficient antecedent basis for this limitation. The lack of antecedent basis arises from claim 17’s dependence from claim 1. Claim 1 does not reference an “adapter element”. While claim 14 recites an “adapter element”, claim 17 does not depend from claim 14.
For purposes of examination, the Examiner is interpreting this claim as referring to how (b) is connected to (a) in instant claim 1.
Claim 33 recites the limitation “wherein said bifunctional antibody is a homodimer with a structure represented by formula Ia.” A claim must be complete by itself and claim 1, upon which claim 33 depends, and claim 33 itself does not set forth the structure of formula Ia. While formula Ia is recited in claim 14, claim 33 does not depend from claim 14 and formula Ia cannot be referred to as set forth in the specification. Therefore, the scope of this claim is indefinite.
For purposes of examination, the Examiner is interpreting claim 33 as depending from claim 14.
Claim 35 recites the limitation “an amino acid sequence” in regards to the heavy chain and light chain. The “an” makes it unclear if this requires the entire amino acid sequence of the named SEQ ID NO, or if only two consecutive recited amino acids within the sequence of the named SEQ ID NO are required for each of the sequences. Therefore, the scope of this claim is indefinite.
Note: This 112(b) rejection can be overcome by amending the claim to say “the amino acid sequence.”
Claim 38 recites the limitation of “said bifunctional antibody is in a form of a drug conjugate.” It is unclear if the claim requires that the bifunctional antibody be conjugated to a drug or if the bifunctional antibody itself is in the form of a drug conjugate. Therefore, the scope of this claim is indefinite.
If applicant intends for a drug to be conjugated to the bifunctional antibody, then the Examiner recommends reciting that the bifunctional antibody is conjugated to a drug.
Claim Rejections - 35 USC § 112(a)
Written Description
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 1-5, 9-10, 14-15, 17, 25-27, 33, 35, and 38-39 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 claim(s) contains 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 inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus. Claim 1 is drawn to a bifunctional antibody, wherein, said bifunctional antibody comprises (a) an anti-PD-L1 antibody or element; and (b) an anti-TGF-β antibody or element connected to said anti-PD-L1 antibody or element. The specification does not provide a limiting definition for “element”.
The claimed genera of “anti-PD-L1 element” and “anti-TGF-β element” must exhibit the function of being anti-PD-L1 and anti-TGF-β. There is no defined structure that correlates to the function, and a sufficient representative number of species have not been described in the specification. The anti-PD-L1 elements and anti-TGF-β elements can include fragments thereof of the claimed anti-PD-L1 and anti-TGF-β antibodies, and can also include proteins, peptides, nucleic acids, small molecules, and any other possible molecule type. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Regarding the encompassed protein and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein. As taught by Skolnick et al., 2000 (instant PTO-892) sequence based methods for predicting protein function are inadequate because of the multifunctional nature of proteins [see Abstract]. Further, just knowing the structure of the protein is also insufficient for prediction of functional sites [see Abstract]. Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cells [page 34, right column]. Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works [page 34, right column].
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al., 1990 (instant PTO-892) who teaches that replacement of a single lysine reside at position 132 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein [see e.g. Abstract] and by Lazar et al., 1988 (instant PTO-892) who teaches that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge et al., 2015 (instant PTO-892) teaches that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference [page E5189, left column]. However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations [page E5196, left column, first paragraph]. The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations [page E5195, right column, last paragraph]. The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible [page E5197, left column, first paragraph]. Additionally, Bork, 2000 (instant PTO-892) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate [page 398, column 1]. One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered [page 398, column 2]. Conclusions from the comparison analysis are often stretched with regard to protein products [page 398, column 3].
Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable [Bork: page 399, column 2]. Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality [see legend for table 1, page 399]. As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search [page 399, paragraph bridging columns 2 and 3]. The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further [page 400, paragraph bridging columns 1 and 2].
One key issue is the prediction of protein function based on sequence similarity. Kulmanov et al., 2018 (instant PTO-892) teaches that there are key challenges for protein function prediction methods [page 661, left column]. These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function [page 661, left column]. Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction [page 661, left column]. Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation [page 661, left column]. Due to these challenges, it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides encompassed by the instant claims [page 661, left column].
Regarding the encompassed antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al., 2002 (instant PTO-892) teaches that even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen [page 416, left column, second paragraph]. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site [page 416, left column, second paragraph – right column, first paragraph]. The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al., 1996 (instant PTO-892) describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region [see Abstract].
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed nucleic acids, the efficacy of any possible DNA or RNA based modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence the expression or function of any target. As taught by Aagaard et al., 2007 (instant PTO-892), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems and therapeutics that are efficient at low doses [see page 79], the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses [see page 79], competition with cellular RNAi components [see page 83], the side effect of suppressing off targets [see page 80], and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al., 1997 (instant PTO-892) teaches that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three dimensional RNA structures [see page 269], while DNA-targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins [see page 269]. These references demonstrate that variation in RNA or DNA based therapeutics will often dramatically affect the biological activity and characteristics of the intended therapeutic. McKeague et al., 2012 (instant PTO-892) teaches that aptamers have particular challenges because unlike antibodies or molecular imprinted polymers, their tertiary structure is highly dependent on solution conditions and they are easily degraded in blood. Further, they have less chemical diversity than other antagonist molecules [see page 2], and have issues associated with determining the Kd measurements for a given molecule [see page 13]. Given the teachings of Aagaard, Warzocha, and McKeague, the claimed nucleic acid therapeutics could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed nucleic acid based therapeutic, such as oligonucleotide aptamers, RNAi molecules and antisense oligonucleotides, would function to decrease expression or function of a target gene or protein, or treat disease.
Regarding the encompassed small molecules, the prediction of function of small molecules is highly unpredictable. According to Guido et al., 2008 (instant PTO-892) accurately predicting the binding affinity of new drug candidates remains a major challenge in drug discovery [see page 37]. There are a vast number of possible compounds that may bind a particular target, many of which have likely not been discovered. Relying on virtual screening also lends unpredictability to the art regarding identification of molecules that would be capable of the required functions of the instant claims. Guido teaches that there are two main complex issues with predicting activity for a small molecule: accurate structural modeling and/or correct prediction of activity [see page 40]. As taught by Clark et al., 2014 (instant PTO-892) even when guided by structural data, developing selective structure-activity relationships has been challenging [see page 5028]. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed small molecule therapeutic would function to inhibit a particular protein or cellular process.
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: …To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claims 2-5, 9-10, 14-15, 17, 25-27, 33, 35, and 38-39, which depend from claim 1, therefore do not meet the written description for the same reasons set forth above.
The Examiner notes that claims 9-10 and 15 do set forth structure for the anti-TGF-β “element” and claims 3-5, 14, 25-27, 33, and 35 require that the bifunctional antibody comprise an anti-PD-L1 antibody and not an anti-PD-L1 “element”. However, taken in total, these claims do not remedy the lack of written description of both the anti-TGF-β element and the anti-PD-L1 element.
Claim 35 is 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 claim(s) contains 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 inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 35 is drawn to a bifunctional antibody comprising an anti-PD-L1 antibody or element and an anti-TGF-β antibody or element connected to said anti-PD-L1 antibody or element, wherein said bifunctional antibody has a heavy chain (H chain) and a light chain (L chain); wherein the H chain of said bifunctional antibody has an amino acid sequence as set forth in SEO ID NO: 1; wherein, the L chain of said bifunctional antibody has an amino acid sequence as set forth in SEO ID NO: 7.
It is possible, given the language of the claim which includes "an amino acid sequence” of SEQ ID NOs: 1 and 7, that any two amino acids in sequence would suffice to meet the limitations of the claims. Because function of any protein, including an antibody, is dependent on the presence of each specific amino acid residue, and with the possibility of added, deleted, or substituted amino acids, a wide variety of antibodies is encompassed by the instant claim. The phrase “an amino acid sequence” allows any fragment, including any two amino acids in sequence, to be encompassed in the instant claim. This would in theory encompass any possible antibody that binds to renalase on earth. These antibodies have no correlation between their structure and function. Amending the claim to recite “the amino acid sequence” would likely overcome the rejection.
The specification teaches that the heavy chain of the bifunctional antibody (protein) has an H chain of SEQ ID NO: 1 and a L chain of SEQ ID NO: 7 [paragraphs 136 and 166]. However, the specification does not teach a functional bifunctional protein or anti-PD-L1 antibody comprising anything less than these full sequences for the H and L chain.
One means of providing adequate written description and evidence of possession of a claimed genus is through providing sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, there is no disclosure for an anti-renalase antibody that only contains an amino acid sequence of only two amino acids for each of six the respective CDRs or for an “antibody mimetic” that specifically binds to renalase. One of skill in the art could not envisage such a structure that would bind to renalase.
The art recognizes that a complete set of six CDRs comprise the binding region of an antibody [see Sela-Culang et al., 2013; instant PTO-892], and that even a single amino acid change to these regions can completely abrogate the binding specificity of an antibody [see Kussie et al., 1994; instant PTO-892]. Thus, making changes to the CDR sequence of an antibody is a highly unpredictable process and the skilled artisan could not a priori make any predictions regarding such changes with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held
that:
...To fulfill the written description requirement, a patent specification must
describe an invention and does so in sufficient detail that one skilled in the art can
clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re
Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the
inventor] invented what is claimed."). Thus, an applicant complies with the written
description requirement "by describing the invention, with all its claimed limitations, not
that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention."
Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
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. 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."). "A
patentee will not be deemed to have invented species sufficient to constitute the genus
by virtue of having disclosed a single species when ... the evidence indicates ordinary
artisans could not predict the operability in the invention of any species other than the
one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir.
2004).
Thus, based on the teachings of the instant specification and the art, Applicant has failed to meet the written description of a bifunctional antibody (protein) that binds to PD-L1 that has any two amino acids in each of H chain and L chain. Therefore, one of skill in the art would not conclude that Applicant was in possession of the claimed invention.
Claim Interpretation
In view of the rejections under 35 U.S.C. 112(a) and 112(b) above, the Examiner will be interpreting the claims for art as if the claims are directed to a bifunctional fusion protein comprising an anti-PDL1 antibody and a TGF-βRII extracellular region, wherein the anti-PDL1 antibody comprises a heavy chain variable region, a heavy chain constant region, a light chain variable region, and a light chain constant region, as set forth in instant claims 9-10, and 14-15 [see paragraphs 129, 135, and Figure 2 of the instant specification supporting this interpretation].
Claim Rejections - 35 USC § 102
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 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 1-5, 9-10, 15, and 17 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Lo (CN106103488; 06/01/2023 IDS).
Regarding claims 1, 9, and 10, Lo teaches a bifunctional protein comprising an antibody or antigen-binding fragment capable of binding to at least part of TGFβ receptor II of TGFβ and an antibody or antigen binding fragment that binds to an immune checkpoint protein (e.g. PDL1) [page 3, fourth paragraph]. Lo further teaches a PDL1 antibody comprising a TGFβ-RII extracellular domain (ECD) (anti-TGFβ element) attached to each CH3 of the antibody [see Figure on page 1; page 2, fifth paragraph].
Regarding claims 2-3 and 5, Lo teaches that the TGFβ-RII ECD is attached to the C-terminus (terminal end) of the heavy chain constant domain [of the PD-L1 antibody] by an amino acid linker (connecting peptide) [see Figure on page 1].
Regarding claim 4, Lo teaches that the soluble fragment capable of binding to TGFβ (e.g. human TGFRII ECD) can be attached by a linker to the N-terminus (initial terminal) of the variable domain [of the PD-L1 antibody] [page 2, fifth paragraph].
Regarding claim 15, Lo teaches that the soluble TGFβ-RII (ECD) comprises SEQ ID NO: 10 [page 13, Example 1; page 21, SEQ ID NO: 10].
SEQ ID NO: 10 of Lo has 100% sequence identity to SEQ ID NO: 2 of the instant claim.
Regarding claim 17, Lo teaches that the TGFβ-RII is fused to the anti-PD-L1 antibody by a flexible (Gly 4 Ser) 4 Gly linker of SEQ ID NO: 11 [page 13, Example 1; page 21, SEQ ID NO: 11].
SEQ ID NO: 11 of Lo has 100% sequence identity to SEQ ID NO: 3 of the instant claim.
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.
Claims 1-5, 9-10, 14-15, 17, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (CN106103488; 06/01/2023 IDS), as applied to claims 1-5, 9-10, 15, and 17 above, and further in view of Vaks et al., 2018 (instant-PTO 892).
The teachings of Lo are above. To reiterate, Lo teaches a bifunctional protein comprising an antibody or antigen-binding fragment capable of binding to at least part of TGFβ receptor II of TGFβ and an antibody or antigen binding fragment that binds to an immune checkpoint protein (e.g. PDL1) [page 3, fourth paragraph] and teaches a PDL1 antibody comprising a TGFβ-RII extracellular domain (ECD) (anti-TGFβ element) attached to each CH3 of the antibody [see Figure on page 1; page 2, fifth paragraph]. Lo further teaches that the TGFβ-RII ECD is attached to the C-terminus (terminal end) of the heavy chain constant domain [of the PD-L1 antibody] by an amino acid linker (connecting peptide) [see Figure on page 1] and that the soluble fragment capable of binding to TGFβ (e.g. human TGFRII ECD) can be attached by a linker to the N-terminus (initial terminal) of the variable domain [of the PD-L1 antibody] [page 2, fifth paragraph]. Lo teaches that the TGFβ-RII is fused to the anti-PD-L1 antibody by a flexible (Gly 4 Ser) 4 Gly linker [page 13, Example 1; page 21, SEQ ID NO: 11].
However, Lo does not teach that there is a disulfide bond between the VH and VL of the anti-PD-L1 antibody.
The Examiner notes that Formulas Ia and Ib do not correspond to the structures depicted in Figure 2 of the instant specification (i.e. HB0028 and HB0029) as the structures in Figure 2 have the disulfide bond between the CL and CH1 and not between the VH and VL.
Regarding claim 14, Vaks teaches that a disulfide bond between the antibodies variable domains that replaces the natural disulfide bond between CH1 and CL provides for effective and correct H-L chain pairing [see Abstract].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the bifunctional protein of Lo to have the disulfide bond between the heavy chain variable domain and light chain variable domain as taught by Vaks, thereby arriving at bifunctional proteins with the structure of Formula Ia and Formula Ib. One would have been motivated to have made this modification because Vaks teaches that a disulfide bond between the variable domains instead of between the heavy chain and light chain constant domains provides for effective and correct H-L chain pairing.
Claim 33 is included in this rejection because Lo teaches that the bifunctional protein can be a homodimer [see Figure on page 1].
Claims 1-5, 9-10, 15, 17, and 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (CN106103488; 06/01/2023 IDS), as applied to claims 1-5, 9-10, 15, and 17 above, and further in view of Yu (CN109929037; instant PTO-892).
The teachings of Lo are above.
However, Lo does not specifically teach that the anti-PD-L1 antibody comprises a VH comprising SEQ ID NOs: 12-14 for the CDRs 1-3, a VL comprising SEQ ID NOs: 15, GIS, and 16 for the CDRs 1-3, and comprises SEQ ID NO: 4 and SEQ ID NO: 8 for the VH and VL, respectively.
Regarding claims 25-27, Yu teaches an anti-human PD-L1 antibody [page 9, third paragraph] and teaches that the amino acid sequence of the heavy chain variable region can comprise SEQ ID NO: 8 and the light chain variable region can be SEQ ID NO: 9 [page 10].
SEQ ID NOs: 8 and 9 of Yu have 100% sequence identity to SEQ ID NOs: 4 and 8, respectively, of instant claim 27 and SEQ ID NOs: 8 and 9 of Yu comprise CDRs 1-3 with 100% sequence identity to SEQ ID NOs: 12-14 for the VH CDRs 1-3, respectively, of instant claim 25, and CDRs 1-3 with 100% sequence identity to SEQ ID NOs: 15, GIS, and 16, respectively, of instant claim 26.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the anti-PD-L1 antibody of Lo to specifically comprise the VH and VL anti-PD-L1 sequences of Yu. One would have been motivated use the sequences of Yu in the bifunctional protein of Lo because Yu teaches that these are sequences of an anti-PD-L1 antibody. Further, one would have been motivated to use the sequences taught by Yu for the anti-PD-L1 antibody of Lo because they are known sequences in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Claims 1-5, 9-10, 15, 17, 25-27, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (CN106103488; 06/01/2023 IDS), as applied to claims 1-5, 9-10, 15, and 17 above, in view of Yu (CN109929037; instant PTO-892), as applied to claims 1-5, 9-10, 15, 17, and 25-27 above, and further in view of Cai (WO2009058797; instant PTO-892) and Spidel (WO2017213267; instant PTO-892).
The teachings of Lo and Yu are above.
However, Lo and Yu do not specifically teach that the bifunctional (protein) has a heavy chain (H chain) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain (L chain) comprising the amino acid sequence of SEQ ID NO: 7.
The following is in regards to the limitations set forth in instant claim 35:
SEQ ID NO: 1 of the instant claim comprises multiple sequences for different components as shown below:
Residues 1-136 correspond to SEQ ID NO: 2 for the TGFβRII-ECD
Residues 137-157 correspond to SEQ ID NO: 3 for the GS linker
Residues 158-277 correspond to SEQ ID NO: 4 for the anti-PD-L1 heavy chain variable region
Residues 278-606 correspond to SEQ ID NO: 5 for the anti-PD-L1 heavy chain constant region
SEQ ID NO: 7 of the instant claim comprises multiple sequence for different components as shown below:
Residues 1-112 correspond to SEQ ID NO: 8 for the anti-PD-L1 light chain variable region
Residues 113-219 correspond to SEQ ID NO: 9 for the anti-PD-L1 light chain constant region
To reiterate the teachings above, Regarding claim 15, Lo teaches a bifunctional protein comprising an anti-PD-L1 antibody linked to a TGFβ-RII ECD, wherein the anti-PD-L1 antibody comprises a VH, VL, CH (CH1-3) and CL [see Figure on page 1], and that the soluble TGFβ-RII (ECD) of the bifunctional protein comprises SEQ ID NO: 10 [page 13, Example 1; page 21, SEQ ID NO: 10], which has 100% sequence identity to SEQ ID NO: 2 of the instant application, and teaches that the TGFβ-RII ECD is fused to the anti-PD-L1 antibody by a flexible (Gly 4 Ser) 4 Gly linker of SEQ ID NO: 11 [page 13, Example 1; page 21, SEQ ID NO: 11], which has 100% sequence identity to SEQ ID NO: 3 of the instant application. Yu teaches an anti-human PD-L1 antibody [page 9, third paragraph] and teaches that the amino acid sequence of the heavy chain variable region can comprise SEQ ID NO: 8 and the light chain variable region can be SEQ ID NO: 9 [page 10], which have 100% sequence identity to SEQ ID NOs: 4 and 8, respectively, of instant application.
Regarding residues 278-606 of SEQ ID NO: 1 for the anti-PD-L1 heavy chain constant region, Cai teaches a heavy chain constant region comprising SEQ ID NO: 91 [page 20, lines 30-32].
SEQ ID NO: 91 of Cai has 100% sequence identity to residues 278-606 of SEQ ID NO: 1 of instant claim 35.
Regarding residues 113-219 of SEQ ID NO: 7 for the anti-PD-L1 light chain constant region, Spidel teaches a kappa light chain constant region comprising SEQ ID NO: 11 [page 1; page 74, Table 9-2].
SEQ ID NO: 11 of Spidel has 100% sequence identity to residues 113-219 of SEQ ID NO: 7 of instant claim 35.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the anti-PD-L1 antibody, as taught by Lo and Yu, to specifically comprise the heavy chain constant region of Cai and the light chain constant region of Spidel. One would have been motivated use the heavy chain constant region of Cai and the light chain constant region of Spidel for the heavy chain constant region and light chain constant region, respectively, of the bifunctional protein as taught by Lo and Yu because they are known sequences in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F). It further would have been obvious to have combined the individual sequences as listed and taught above by the respective art of Lo, Yu, Cai and Spidel, to arrive at SEQ ID NOs: 1 and 7 of the instant claim. One would have been motivated to have used these sequences for each of the components that form SEQ ID NOs: 1 and 7 because they are known sequences in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Claims 1-5, 9-10, 15, 17, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (CN106103488; 06/01/2023 IDS), as applied to claims 1-5, 9-10, 15, and 17 above, and further in view of Casi et al., 2012 (instant PTO-892).
The teachings of Lo above.
However, Lo does not specifically teach that the bifunctional antibody (protein) is conjugated to a drug (in the form of a drug conjugate).
Regarding claims 38 and 39, Casi teaches antibody-drug conjugates [see page 425, Table 3] and that antibody-drug conjugates combine the desirable properties of antibodies with the cell killing activity of cytotoxic drugs, reducing systemic toxicity and increasing the therapeutic benefit of patients [see Abstract].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the bifunctional protein of Lo, which comprises an anti-PD-L1 antibody, to be conjugated to a drug, thereby forming an antibody-drug conjugate, as taught by Casi. One would have been motivated to have modified the bifunctional protein of Lo to be conjugated to a drug, thereby forming an antibody-drug conjugate because Casi teaches that antibody-drug conjugates combine the desirable properties of antibodies with the cell killing activity of cytotoxic drugs, reducing systemic toxicity and increasing the therapeutic benefit of patients.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
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, Jeffrey Stucker can be reached at (571) 272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
Prosecution Insights