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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on September 30, 2025 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on September 30, 2025. Claims 1 and 13-14 have been amended. Claims 5 and 30-31 are canceled.
Therefore, claims 1-4 and 6-29 are currently under examination.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/US20/35667, filed on June 02, 2020. Applicants' claims benefit of a prior filed application parent provisional application 62/856, 168, filed June 03, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c).
Thus, the earliest possible priority for the instant application is June 03, 2019.
Withdrawn- Abstract Objection
Upon further consideration, the objection to the abstract is withdrawn.
Maintained & Modified Claim Rejections - 35 USC § 103
Claims 1-4 and 6-12 and 25-29 remain rejected under 35 U.S.C.103 as being unpatentable over Crystal et al. (US 10,214,731 B2; references are to prior publication US 2016/0347822 Al), in view of Kraus et al. (US 2004/0033219 Al; hereinafter 'Oliveriusova'), Kraus et al. (US 5,523,225; hereinafter 'Kraus'), and Kraus et al. (US 9,675,678 B2; hereinafter 'Bublil'), Bancel et al. (US 2014/0010861 Al), Raymaekers et al. J Clin Lab Anal. 2009;23(3):145-51, and further in view of Kwok et al. (PCR Methods Appl. 1994 Feb;3(4): S39-47), Green et al. (PLoS One. 2015 May 21;10(5): e0128122. eCollection 2015), and Stadhouders et al. (J Mol Diagn. 2010 Jan;12(1):109-117. This is a modified rejection necessitated by amendment of the claims in the response filed September 30, 2025.
Regarding the applicants’ amendment to claim 1 introducing the recitation of an exogenous nucleic acid sequence encoding a full-length human Cystathionine-synthase (hCBS) polypeptide, Oliveriusova teaches recombinant human cystathionine-β-synthase (CBS) polypeptides and nucleic acid molecules encoding the same, including the wild-type human CBS sequence (SEQ ID NO: 2 and claims 1 and 57), and therefore teaches expression of the full-length hCBS polypeptide. Further, Oliveriusova expressly discloses recombinant expression constructs and promoter-controlled expression of CBS coding sequences ([0101-0104]). Although Oliveriusova additionally evaluates truncated CBS variants, the reference nevertheless teaches and utilized the corresponding full-length human CBS sequence as a starting construct and comparison control, thereby demonstrating the possession and recognition of the full-length hCBS polypeptide in the prior art.
Moreover, Bublil teaches a codon-optimized full-length human CBS coding sequence encoding the complete 551 amino acid human CBS protein and describes recombinant constructs containing the full-length hCBS coding region for expression and characterization purposes (column 7, para. 1-5; column 23, lines 33-39). Thus, the combined teachings of Oliveriusova and Bublil demonstrate that full-length hCBS polypeptides and nucleic acid sequences encoding the same were well known in the art prior to applicant’s effective filing date. Therefore, it would have been obvious to one of ordinary skill in the art to employ the known full-length hCBS coding sequence taught by Oliveriusova and Bublil in the recombinant AAV expression system of Crystal to obtain the predictable result of expressing full-length hCBS from an AAV vector with a reasonable expectation of success.
Furthermore, regarding claim 1, Crystal teaches a recombinant adeno-associated virus (AAV) nucleic acid molecule comprising a CMV early enhancer/chicken beta actin (CAG) promoter (column 2, lines 48-53, Fig. 3A and column 8, para. 2). Regarding the limitation that the CAG promoter and the exogenous nucleic acid sequence encoding the hCBS polypeptide are surrounded by AAV Inverted Terminal Repeats (ITRs), Crystal additionally teaches where the nucleic acid sequence encoding the polypeptide is surrounded by AAV Inverted Terminal Repeats (ITRs) (Fig. 3A) in addition to where the AAV ITRs flank the unique coding nucleotide sequences (column 4, lines 33-36 and column 12, Example 2).
Crystal does not teach where the promoter operably linked to an exogenous nucleic acid sequence encoding a human Cystathionine β-synthase (hCBS) polypeptide.
However, Oliveriusova teaches human cystathionine β-synthase variants and method to produce recombinant human cystathionine β-synthase and variants thereof (abstract and claims 1, 57). Furthermore, Oliveriusova teaches the integrated nucleic acid molecule can be under chromosomal promoter control, under native or plasmid promoter control, or under a combination of several promoter controls ([0101]), and important transcription control sequences are those which control transcription initiation, such as promoter, enhancer, operator and repressor sequences ([0104]).
Prior to the effective filing date, the ordinary artisan would have found it obvious to combine the prior art elements of a recombinant adeno-associated virus (AAV) nucleic acid molecule comprising a CMV early enhancer/chicken beta actin (CAG) promoter, as taught by Crystal, by operably linking to an exogenous nucleic acid sequence encoding a human Cystathionine β-synthase (hCBS) polypeptide, as taught by Oliveriusova, to yield the predictable result of obtaining an effective AAV expression vector with suitable construct.
Regarding claim 2, the combined teachings of Crystal and Oliveriusova render claim 1 obvious. Additionally, Oliveriusova teaches the exogenous amino acid sequence (pg. 29, SEQ ID NO 2) of a hCBS polypeptide comprising an ammo acid sequence 100% identical to the amino acid sequence of SEQ ID NO: 1.
Regarding claim 3, the combined teachings of Crystal and Oliveriusova render claim 1 obvious. The combined teachings of Crystal and Oliveriusova do not teach the exogenous nucleic acid sequence comprises a nucleotide sequence at least 85% identical to the nucleotide sequence of SEQ ID N0:2.
However, Kraus teaches an isolated DNA sequence encoding human cystathionine β-synthase, a composition of human cystathionine P-synthase in a pharmacologically acceptable carrier for treating a human suffering from homocystinuria (abstract), and the exogenous nucleic acid sequence comprises a nucleotide sequence (pg. 14-16, SEQ ID NO 1) 96% identical to the nucleotide sequence of SEQ ID N0:2.
Prior to the effective filing date, the ordinary artisan would have found it obvious to simply substitute the known element of the exogenous nucleic acid sequence comprises a nucleotide sequence at least 85 % identical to the nucleotide sequence of SEQ ID N0:2, as taught by Kraus, corresponding to the hCBS polypeptide encoded for and taught by Oliveriusova, along with the recombinant adeno-associated virus (AAV) nucleic acid molecule comprising a CMV early enhancer/chicken beta actin (CAG) promoter, as taught by Crystal. This simple substitution would have obtained the predictable result of generating a recombinant adeno-associated virus (AAV) nucleic acid molecule comprising a CMV early enhancer/chicken beta actin (CAG) promoter operably linked to an exogenous nucleic acid sequence encoding a human Cystathionine β-synthase (hCBS) polypeptide, with a reasonable expectation of success.
Regarding claim 4, the combined teachings of Crystal and Oliveriusova render claim 1 obvious. Additionally, Crystal teaches a number of polynucleotides comprising promoters (such as the commonly used CMV promoter and also comprise enhancer sequences where the enhancers are located upstream (column 8, para. 2).
Regarding claim 6, the combined teachings of Crystal and Oliveriusova render claim 1 obvious. Additionally, Crystal teaches where the expression of the AAV nucleic acid molecule is encoded by the AAV plasmid in cells (column 2, lines 54-56, FIG. 3B). Crystal also expressly states the vector of the invention can comprise, consist essentially of, or consist of any gene transfer vector known in the art. Examples of such vectors include adeno-associated viral (AAV) vectors, adenoviral vectors, lentiviral vectors, retroviral vectors, and plasmids (column 4, lines 9-14 and column 12, Example 2).
Regarding claim 7, the combined teachings of Crystal and Oliveriusova render claim 1 obvious. Additionally, Oliveriusova teaches the method enables one to amplify a CBS cDNA fragment spanning the desired nucleotide residues ([0180]), using site-directed mutagenesis, using a pair of custom designed primers ([0175]). Furthermore, Crystal teaches a large number of enhancers from a variety of different sources are well known in the art and are available as or within cloned polynucleotides (from, e.g., depositories such as the ATCC as well as other commercial or individual sources), using hairpin structures which function as an origin for viral DNA replication by serving as primers for the cellular DNA polymerase complex (column 4, lines 39-41 and column 11, para. 3-4). Moreover, Crystal expressly teaches the optimized full length human cDNA sequence was synthesized and cloned into the pAAV plasmid-under control of the CAG promoter for vector replication (column 12, Example2).
Regarding claim 8, the combined teachings of Crystal and Oliveriusova render claim 1 and 7 obvious.
The combined teachings of Crystal and Oliveriusova do not teach where the source containing the exogenous nucleic acid sequence is pUC: ΔHCBS.
However, Bublil teaches the full length (551 aa) human CBS coding sequence was optimized for bacterial expression and cloned into a p UC vector, specifically the species p UC57 plasmid (column 23, Example 1, lines 33-37).
Prior to the effective filing date of the instant application, the ordinary artisan would have found it obvious to use the known technique of utilizing a p UC plasmid containing the exogenous nucleic acid sequence hCBS, as taught by Bublil, to improve the similar methodologies utilizing plasmids for exogenous nucleic acid sequence integration, as taught by Crystal and Oliveriusova, in the same way. Furthermore, the selection of a plasmid for such routine biomolecular applications is deemed merely a matter of judicious selection and routine optimization that is well within the purview of the skilled artisan. This is supported by the instant applications recognition that "in some embodiments, the source containing the exogenous nucleic acid sequence is p UC: L1HCBS, which is commercially available or can be obtained through RT-PCR of RNA derived from human tissue, or can be chemically synthesized (pg. 14, lines 24-26).
Regarding claim 9, the combined teachings of Crystal and Oliveriusova render claim 1 and 7 obvious. Additionally, Crystal teaches the utilization of amplification by PCR using primers flanking the mutation target region using forward and reverse primers, and PCR amplification was performed with Taq polymerase and reagents supplied (column 11, para. 3-4).
While the combined teachings of Crystal and Oliveriusova do not teach the specific primer comprising the nucleotide sequence of SEQ ID N0:3 or SEQ ID N0:4 for preparing the recombinant AAV nucleic acid molecules by amplifying the exogenous nucleic acid sequence and cloning, the ordinary artisan would have found it obvious to try primer optimization for the given sequence, choosing from a finite number of identified, predictable primer sequence complements, with a reasonable expectation of success.
A person of ordinary skill in the art would have found it obvious to obvious to try optimizing primers for the target sequence, choosing from a finite number of identified, predictable solutions. This would have been accomplished with a reasonable expectation of success, further in view of Bancel which teaches SEQ ID NO: 7229 with 2583 base length and 100% homology to the target sequence, instant application's SEQ ID NO: 2.
Prior art consistently recognized and teaches that optimizing these factors enhances specificity and efficiency in PCR, making such modifications predictable and routine, rather than novel or non-obvious for instance, and further in view of, Raymaekers teaching of methods of RT-PCR validation, primer optimization, and the use of optimal primer and probe sequences being one of the critical steps for a successful PCR (pg. 146, column 2, Section: Choice of oligonucleotides). The optimization of bimolecular primers by adjusting parameters such as GC content, melting temperatures (Tm), and length would have been obvious to try for a person of ordinary skill in the art, as these variables are well-known to affect primer binding, stability, and amplification efficiency in PCR. Routine experimentation with these parameters, is supported by established design guidelines and tools would have provided a reasonable expectation of success in improving amplification outcomes.
Moreover, an analysis of the primers of SEQ ID NO: 3 and SEQ ID NO:4 shows that the target SEQ ID NO: 2, with 100% homology to the sequence taught by Bancel, contains primer sites (82% and 100% best local similarity) sufficient for the binding of the target. The prior art rife with teachings recognizing that primer design along with specific amplification variables, such as temperature or the design of the cycle can accommodate mismatches and primer degeneracies and are sometimes preferred for the procedural aims of the reaction, further in view of the teachings of Kwok (pg. 541, Sections: Mismatch Tolerance and Degenerate Primers), Green (pg. 17, para. 2), and Stadhouders (pg. 115, para. 3-7).
Regarding claim 10, the combined teachings of Crystal and Oliveriusova render claim 1 and 7 obvious. Additionally, Oliveriusova teaches the use of multiple cloning sites (MSC) in the method to recombinantly produce and purify a human cystathionine β-synthase ([0111], [0113], and [017 5]). The instant applications specification clarifies that the MCS, in pAAV-CAG-MCS, is a multiple cloning site that facilitates the insertion of the desired gene to be expressed (pg. 14, lines 31-34).
Regarding claim 11, the combined teachings of Crystal and Oliveriusova render claim 1 obvious. Additionally, Crystal teaches the AAV ITRs flank the unique coding nucleotide sequences for the non-structural replication (Rep) proteins and the structural capsid (Cap) proteins (also known as virion proteins (VPs)), specifically the cap genes encode the capsid proteins VP1, VP2, and VP3 (column 4, para. 4).
Regarding claim 12, the combined teachings of Crystal and Oliveriusova render claim 1 and 11 obvious. Additionally, Crystal teaches the AAV vector can be generated using any AAV serotype known in the art, including AAV serotype Rh10 (column 4, lines 55- column 5, line 5).
Regarding claim 25-26, the combined teachings of Crystal and Oliveriusova render claims 1 and 11 obvious. Additionally, Crystal teaches a composition comprising, consisting essentially of, or consisting of the above-described vector and a pharmaceutically acceptable (e.g., physiologically acceptable) carrier. When the composition consists essentially of the inventive vector and a pharmaceutically acceptable carrier, additional components can be included that do not materially affect the composition (e.g., adjuvants, buffers, stabilizers, anti-inflammatory agents, solubilizers, preservatives, etc.) (column 8, para. 3).
Regarding claim 27-28, the combined teachings of Crystal and Oliveriusova render claims 1, 11, and 26 obvious. Additionally, Oliveriusova teaches the method is used to treat the disorder homocystinuria (claims 30-31), a CBS deficiency ([0004] and [0030]).
Regarding claim 29, the combined teachings of Crystal and Oliveriusova render claims 1, 11, and 26 obvious. Additionally, Oliveriusova teaches the therapeutic composition is administered to a patient in a manner effective to deliver the composition to a cell, a tissue, and systemically to the patient, whereby the desired result is achieved as a result of the administration of the composition, including intramuscular and intravenous injection ([0128]).
***
Claims 13-24 remain rejected under 35 U.S.C.103 as being unpatentable over Crystal et al. (US 10,214,731 B2; references are to prior publication US 2016/0347822 A1), in view of Kraus et al. (US 2004/0033219 Al; hereinafter' Oliveriusova'), Rosenberg et al. (Hum Gene Ther Clin Dev. 2018 Mar 1;29(1):24-47.), and Potter et al. (US 2017/0130208 A1). This is a modified rejection necessitated by amendment of the claims in the response filed September 30, 2025.
Regarding the applicants’ amendment to claims 13-14 introducing the recitation of an exogenous nucleic acid sequence encoding a full-length human Cystathionine-synthase (hCBS) polypeptide, Oliveriusova teaches recombinant human cystathionine-β-synthase (CBS) polypeptides and nucleic acid molecules encoding the same, including the wild-type human CBS sequence (SEQ ID NO: 2 and claims 1 and 57), and therefore teaches expression of the full-length hCBS polypeptide. Further, Oliveriusova expressly discloses recombinant expression constructs and promoter-controlled expression of CBS coding sequences ([0101-0104]). Although Oliveriusova additionally evaluates truncated CBS variants, the reference nevertheless teaches and utilized the corresponding full-length human CBS sequence as a starting construct and comparison control, thereby demonstrating the possession and recognition of the full-length hCBS polypeptide in the prior art. Thus, the teachings of Oliveriusova demonstrate that full-length hCBS polypeptides and nucleic acid sequences encoding the same were well known in the art prior to applicant’s effective filing date. Therefore, it would have been obvious to one of ordinary skill in the art to employ the known full-length hCBS coding sequence taught by Oliveriusova in the recombinant AAV expression system of Crystal to obtain the predictable result of expressing full-length hCBS from an AAV vector with a reasonable expectation of success.
Furthermore, regarding claims 13-15, Crystal teaches the method of producing an expression cassette consisting of the AAV inverted terminal repeats (ITR), encapsidation signal, cytomegalovirus (CMV) enhancer chicken-~-actin promoter (CAG promoter) operably linked to a human C1E1 cDNA sequence. Additionally, Crystal teaches optimized full length human C1E1 cDNA sequence was synthesized and cloned into the pAAV plasmid-under control of the CAG promoter. The AAV-hC1E1 plasmid was produced by co-transfection into human embryonic kidney 293T cells (HEK 293T; American Type Culture Collection) of the pAAV plasmid together with a plasmid carrying the AAV Rep proteins derived from AAV2 needed for vector replication, the AAVrh.10 viral structural (Cap) proteins VP1, 2 and 3, which define the serotype of the produced AAV vector; and the adenovirus helper functions of E2, E4 and VA RNA. Regarding the limitation that the CAG promoter and the exogenous nucleic acid sequence encoding the hCBS polypeptide are surrounded by AAV Inverted Terminal Repeats (ITRs), Crystal additionally teaches where the nucleic acid sequence encoding the polypeptide is surrounded by AAV Inverted Terminal Repeats (ITRs) (Fig. 3A) in addition to where the AAV ITRs flank the unique coding nucleotide sequences (column 4, lines 33-36 and column 12, Example 2).
Crystal does not teach where the human cDNA sequence is human CBS.
However, Oliveriusova teaches a method to produce a recombinant human cystathionine β-synthase. The method includes a first step of: (a) transfecting a recombinant host cell with a recombinant nucleic acid molecule comprising a first nucleic acid sequence encoding a human cystathionine β-synthase or homologue thereof having human cystathionine β-synthase biological activity, wherein the recombinant nucleic acid molecule comprises a recombinant expression vector operatively linked to the first nucleic acid sequence ([0031]).
Prior to the effective filing date, it would have been obvious to the ordinary artisan to have simply substituted the nucleic acid sequence encoding a human cystathionine β-synthase, as taught by Oliveriusova, for the C1E1 cDNA sequence, as taught by Crystal to obtain the predictable method of method of producing a recombinant AAV vector comprising cotransfecting a host cell with CAG-hCBS DNA surrounded by AAV ITRs and a helper nucleic acid molecule that comprises the AAV Rep and Cap sequences and adenovirus helper functions E4, E2a and VA; and culturing the host cell for a period of time sufficient to produce the recombinant AAV vector. Methods of altering an AAV vector were well known in the art, as recognized by the instant applications specification stating "methods of altering the AAV vector may involve a variety of techniques, which techniques are known to those of skill in the art. For example, site directed mutagenesis may be 5 performed at the level of the nucleic acids encoding one or more amino acids to be altered. Alternately, an insertion of one or more amino acids (e.g., 2, 3, 4, 5 or more) may be made at the target region within the AAV capsid (pg. 21, lines 3-7)." Concerning the recitation in claim 14 of a first and second helper nucleic acid and claim's 15 reordering of the transfection components, Crystal teaches AAV requires coinfection with a helper virus (i.e., an adenovirus or a herpes virus), or expression of helper genes, for efficient replication (column 4, lines 17-20), as well as the utility of Rep, Cap, and the helper functions of E4, E2, and VA. Furthermore, "When a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297,301 (CCPA l 982) ("Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious"). In this case, all of the transfection elements were well known in the art, and it would have been obvious to try optimizing the structural design, absent any evidence to the contrary.
Regarding claim 16-17, the combined teachings of Crystal and Oliveriusova render claim 13 obvious. Additionally, Crystal teaches the rep sequences and ITRs of many AAV serotypes are known to efficiently cross-complement (i.e., functionally substitute) corresponding sequences from other serotypes during production of AAV particles in mammalian cells (column 5, lines 24-28), as well as the method of co-transfection of human embryonic kidney 293T cells, HEK 293Tand Adenovirus El helper function (column 12, line 58).
Regarding claim 18-19, the combined teachings of Crystal and Oliveriusova render claim 13 and 16 obvious. The combine teachings of Crystal and Oliveriusova do not teach where the helper nucleic acid molecule is a helper plasmid pPAKMArh.10.
However, Rosenberg teaches AAVrh.10 vector production by co-transfection of two plasmids: one coding for the therapeutic gene (pAAV2-CAG-hAPOE2-HA), and the other providing AAV replication and capsid functions plus the adenoviral helper functions (pPAK-MArh.10) into a stable human embryonic kidney cell line (293T) (pg. 25, column 2, para. 2, Section: Gene transfer vector).
Prior to the effective filing date of the instant application, it would have been obvious to the ordinary artisan to have used the know, technique of utilizing the helper packaging plasmid pPAKMArh.10 for co-transfection, as taught by Rosenberg, to improve the similar method of pAAV-CAG-hCBS co-transfection, as taught by the combined teachings of Crystal and Oliveriusova, in the same way. In doing so, the ordinary artisan would have had a reasonable expectation of optimizing vector replication.
Regarding claims 20-24, the combined teachings of Crystal and Oliveriusova render claim 13 obvious. Additionally, Oliveriusova teaches the assaying of cell lysate ([0159] and Examples 2-5).
The combined teachings of Crystal and Oliveriusova do not teach wherein the host cell is the insect cell Sf9 and the DNA is surrounded by AAV ITRs is present in a baculovirus or a Bacmid.
However, Potter teaches compositions and methods related to purification of recombinant adeno-associated virus (rAAV) particles wherein the cell lysate is a mammalian or insect cell lysate. In some embodiments of any one of the methods provided herein, the cell lysate is HEK293 or Sf9 producer cell lysate (claims 1, 11-12, [0016], [0035], and [0052]). Furthermore, Potter teaches where Sf9-based producer stable cell lines are infected with a single recombinant baculovirus containing the rAAV expression cassette ([0076-0077], [0109], and [0113]).
Before the effective filing date of the instant application, it would have obvious for the ordinary artisan to combine the prior art elements of a method utilizing a Sf9 insect host cell and purifying the viral vector from lysate, as taught by Potter, with the similar methods of AAV vector production in a host cell and lysate assaying, as taught by Crystal and Oliveriusova, to yield the predictable result of obtaining a methodology of producing an AAV vector with cotransfecting a host cell with CAG-hCBS DNA surrounded by AAV ITRs in the given cell type, with a reasonable expectation of success.
Response to Applicants’ arguments as they apply to the rejection of Claims 1-4 and 6-29 under 35 USC § 103
Applicant's arguments filed September 30, 2025, have been fully considered but they are not persuasive.
At pages 8-12 of the remarks filed on September 30, 2025, Applicants essentially argue the following:
Applicant argues that the cited references teach away from the claimed invention because the art allegedly favored truncated CBS variants over full-length hCBS due to enhanced activity and reduced aggregation, and therefore a person of ordinary skill in the art would not have selected a full-length hCBS sequence for use in an AAV expression system nor possessed a reasonable expectation of successfully expressing therapeutically effective full-length hCBS in vivo.
This argument is not persuasive because the cited references do not expressly discourage the use of full-length hCBS sequence. Rather, the references expressly disclose the full-length hCBS sequence and utilize the full-length enzyme as a known and functional protein. The mere disclosure of alternative embodiments, including variants possessing certain advantageous properties, does not constitute a teaching away from other disclosed embodiments.
In the instant case, the disclosures addressed full-length embodiments. The Examiner respectfully submits that patents are relevant as prior art for all they contain. "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983). With that, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, even nonpreferred embodiments. See MPEP § 2123: Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989); Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Furthermore, the argument is not persuasive because the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence, and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
Claims 1-4 and 6-29 are rejected. No claims are allowed.
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/J.D.L./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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