Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 1 of 24 PageID #: 22799
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`IMPOSSIBLE FOODS INC.,
`
`Plaintiff,
`
`v.
`
`MOTIF FOODWORKS, INC., and
`GINKGO BIOWORKS, INC.,
`
`
`
`Defendants.
`
`
`
`
`
`Case No. 1:22-cv-00311-WCB
`
`
`
`
`
`DECLARATION OF DR. CARL BATT IN SUPPORT OF
`GINKGO BIOWORKS, INC.’S REPLY CLAIM CONSTRUCTION BRIEF
`
`
`

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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 2 of 24 PageID #: 22800
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`TABLE OF CONTENTS
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`Background ......................................................................................................................... 1
`Opinions .............................................................................................................................. 1
`A.
`Term 1 - “promoter element” .................................................................................. 1
`1.
`Dr. Alper does not identify what sequences are included in the meaning of
`the term “promoter element” ...................................................................... 2
`The specification does not disclose what sequences are included in the
`meaning of the term “promoter element” ................................................... 4
`The art cited by Dr. Alper does not show that the POSA would be able to
`determine the scope of “promoter element” with any reasonable certainty 6
`Term 2a - “a Mxr1 transcriptional activator sequence” (’492 Patent, claim 1) .... 15
`Term 6 - “sequence to which [the/a] Mxr1 transcriptional activator binds” ........ 19
`
`2.
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`3.
`
`I.
`II.
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`
`
`B.
`C.
`
`i
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`

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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 3 of 24 PageID #: 22801
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`I, Carl Batt, Ph.D., hereby declare:
`
`I.
`
`BACKGROUND
`
`1.
`
`I have been asked by counsel for Ginkgo Bioworks, Inc. (“Ginkgo”) to review
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`and, address certain portions of declarations of Dr. Hal Alper and Dr. Geoffrey Lin-Cereghino,
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`submitted by Impossible Foods Inc. (“Impossible”) and Motif Foodworks Inc. (“Motif”),
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`respectively, on January 26, 2024 in support of their respective claim construction briefs.
`
`2.
`
`My opinions expressed in this declaration are based on my review of Dr. Alper
`
`and Dr. Lin-Cereghino’s declarations, the exhibits attached to those declarations, Dr. Alper’s
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`prior declaration filed June 14, 2023, Dr. Alper’s prior declaration filed July 7, 2023, and the
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`additional materials referenced and discussed below.1 I also base my opinions upon my own
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`knowledge and skill as an expert in the field.
`
`3.
`
`In formulating the opinions set forth below, I have applied the same
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`understanding of legal principles set forth in my declaration of January 12, 2024.
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`4.
`
`I am being compensated at my customary rate of $425 per hour for my work in
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`this matter. This compensation is in no way contingent upon the outcome of this matter or upon
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`the opinions I offer in this declaration. All of the opinions expressed in this declaration are my
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`own.
`
`II.
`
`OPINIONS
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`Term 1 - “promoter element”
`
`Term 1 and the constructions proposed by Ginkgo, Motif, and Impossible are
`
`A.
`
`5.
`
`below.
`
`
`1 I understand that Impossible referred to Dr. Alper’s three declarations as “Alper I” (for the June
`14, 2023 declaration), Alper II (for the July 7, 2023 declaration) and “Alper III” (for the January
`26, 2024 declaration). I refer to them in the same way below for ease of reference.
`
`1
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`

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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 4 of 24 PageID #: 22802
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`Impossible’s Proposed
`Construction
`
`Plain and ordinary meaning. No
`construction is necessary.
`
`To the extent that this term is
`construed:
`a polynucleotide that regulates
`(e.g., drives) transcription of a
`polynucleotide sequence (e.g.,
`gene)
`
` promoter element is upstream
`of, and adjacent to or in close
`physical proximity to the gene
`
`
` a
`
`Term
`No.
`
`1
`
`Claim Term
`
`“promoter element”
`
`(’492 Patent, all asserted
`claims; ’656 Patent, all
`asserted claims)
`
`Ginkgo’s / Motif’s
`Proposed
`Construction
`indefinite
`
`6.
`
`I also understand that Impossible previously stated that the term “promoter
`
`element” refers to “something that modulates, directs or regulates expression,” but has recently
`
`changed its proposed construction to be “a polynucleotide that regulates (e.g., drives)
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`transcription of a polynucleotide sequence (e.g., gene),” including that “a promoter element is
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`upstream of, and adjacent to or in close physical proximity to the gene.”
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`7.
`
`For the reasons outlined below, it is still my opinion that a POSA would conclude
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`that the term “promoter element” is indefinite in the claims of the ’492 and ’656 Patents (the
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`Yeast Patents). In the context of the Yeast Patents, the term “promoter element” fails to inform a
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`POSA with reasonable certainty about the scope of the alleged invention.
`
`1.
`
`Dr. Alper does not identify what sequences are included in the
`meaning of the term “promoter element”
`
`8.
`
`Dr. Alper does not discuss Impossible’s claim construction. Instead, his January
`
`26, 2024 declaration states that Impossible’s construction is “plain and ordinary meaning.”
`
`Alper III at page 6. But as his opinions confirm, the term “promoter element” is used differently
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`in different contexts, with the result that the scope of the term as used in the claims of the Yeast
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`2
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`

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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 5 of 24 PageID #: 22803
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`Patents is not reasonably certain.
`
`9.
`
`Dr. Alper states several times that the term “promoter element” is well
`
`understood, but he does not provide any definition of the boundaries of the term other than with
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`respect to its function. For example, he states that a “promoter element” would be “a nucleic
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`acid sequence that drives transcription of the gene.”2 Elsewhere he provides a different (broader)
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`explanation of what he believes a promoter element to be: “it is a polynucleotide sequence, it
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`regulates (e.g., modulates, drives, directs) expression (which includes transcription) of a
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`polynucleotide sequence (e.g. a gene).”3 He then states “a POSA understands what that
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`structure[4] is with reasonable certainty.”5 Despite this statement, Dr. Alper never actually
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`identifies what specific sequence, or classes of sequences are necessary or sufficient,
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`independent of the surrounding sequences, for it to be considered a “promoter element.”
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`10.
`
`As I explained in my January 12, 2024 declaration, whether a particular sequence
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`modulates, directs, or regulates expression cannot be determined by knowledge of the sequence
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`alone.6 Context—including the surrounding sequences, the locations of those sequences relative
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`to a gene to be expressed, and the host organism—plays a significant role in whether any
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`particular sequence will perform the function of “promoter element” identified by Dr. Alper. Dr.
`
`Alper does not dispute this.7
`
`11.
`
`Dr. Alper also opines that “the claims simply require operably linking a promoter
`
`
`
`2 Alper III ¶ 27.
`3 Alper III ¶ 30.
`4 I understand that by “structure” here, Dr. Alper is referring to the legal term, rather than the
`term as used in the molecular biology field.
`5 Alper III ¶ 30.
`6 I discussed this in my January 12, 2024 report at paragraphs 69-78.
`7 Alper III ¶ 35.
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`3
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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 6 of 24 PageID #: 22804
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`element to a nucleic acid such that it may drive transcription,”8 not that it must drive
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`transcription. To the extent that this is Dr. Alper’s opinion, it provides another reason that the
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`scope of the claim term “promoter element” would not be reasonably certain to the POSA.
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`Further, the POSA could not distinguish where the putative “promoter element” ends and what
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`sequence or sequences should be considered “dispensable” (to use Dr. Alper’s language9) and
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`thus not part of the promoter element, a determination that might depend on numerous unknown
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`contextual factors. As discussed below, the specification of the Yeast Patents does not provide
`
`any guidance that would allow the POSA to make these determinations with any reasonable
`
`certainty.
`
`2.
`
`The specification does not disclose what sequences are included in the
`meaning of the term “promoter element”
`
`12.
`
`Dr. Alper opines that “the patents explain that promoter elements were known in
`
`the art and are commonly used to drive transcription of genes,” citing to the ’656 patent at 6:36-
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`37 and 4:60-5:11.10 I disagree.
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`13.
`
`The first citation to 6:36-37 is a statement that “constitutive promoters and
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`constitutive promoter elements are known in the art” without further elaboration. This passage is
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`consistent with my opinion that in the context of the Yeast Patents, a promoter element is
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`different from a promoter.11 Otherwise, this passage provides no information on the scope of the
`
`term “promoter element.” And while I agree that constitutive promoters are known in the art, I
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`disagree that “constitutive promoter elements” are known in the art, because there is no
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`consensus understanding as to what a “constitutive promoter element” is in vacuo.
`
`
`8 Alper III ¶ 37 (emphasis added).
`9 Alper III ¶ 28.
`10 Alper III ¶ 34.
`11 I discuss this at paragraphs 65-68 f my prior declaration.
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`4
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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 7 of 24 PageID #: 22805
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`14.
`
`As to the second citation to 4:60-5:11, the material Dr. Alper references is below
`
`(emphasis is mine):
`
`Other methanol-inducible promoters, or promoter elements
`therefrom, however, can be used, including, without limitation,
`the alcohol oxidase (AOD1) promoter from Candida boidinii (see,
`for example, GenBank Accession No. YSAAOD1A), the alcohol
`oxidase (MOX) promoter from Hansenula polymorpha (see, for
`example, GenBank Accession No. X02425), the MOD1 or MOD2
`promoter from Pichia methanolica (see, for example, Raymond et
`al., 1998, Yeast, 14:11-23; and Nakagawa et al., 1999, Yeast,
`15:1223-30), the DHAS promoter from P. pastoris (see, for
`example, GenBank Accession No. FJ752551) or a promoter
`element therefrom, the formaldehyde dehydrogenase (FLD1)
`promoter from Pichia pastoris (see, for example, GenBank
`Accession No. AF066054), or the PEX8 promoter from P. pastoris
`(see, for example, Kranthi et al., 2010, Yeast, 27:705-11). In some
`embodiments, the transcriptional activator is a Mit1 sequence from
`Pichia pastoris (see, for example, GenBank Accession No.
`CAY70887). All of these promoters are known to be induced by
`methanol.
`
`15.
`
`The term “promoter element” is used only twice in this passage. Other than in
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`general (at the beginning) or when discussing the DHAS promoter “or a promoter element
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`therefrom,” this passage refers exclusively to promoters, and provides sequence information for
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`the complete promoters. With respect to DHAS, as I discussed in detail in my January 12, 2024
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`declaration, there is no guidance in the Yeast Patents as to which subset of the 980 nucleotides of
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`the referenced DHAS promoter constitutes a “promoter element therefrom,” by function,
`
`sequence, or anything else.12
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`16. Moreover, the “promoter element therefrom” language is only specifically linked
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`to the DHAS promoter. The complete AOD1, MOX, MOD1, MOD2, FLD1, and PEX8
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`promoters are referenced, but there is no specific reference to promoter elements from any of
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`these complete promoters. The POSA would not be certain whether these promoters contain
`
`
`12 I discussed this in paragraphs 72-73 of my January 12, 2024 declaration.
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`5
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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 8 of 24 PageID #: 22806
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`promoter elements, or, if they did, whether any such promoter elements were the type of
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`“promoter element” contemplated by the claims. This passage of the specification then refers to
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`the Mit1 sequence, which is not a promoter or promoter element at all. It is a transcriptional
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`activator protein. For these reasons, the POSA would find this portion of the specification
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`somewhat confusing, but at minimum, it would not provide a POSA with any reasonable
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`certainty as to the scope of the term “promoter element.”
`
`17.
`
`Dr. Alper also states that the Yeast Patents “provide[] multiple working examples
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`of promoter elements that drive transcription,” citing to Example 22 and 25 of the Yeast
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`Patents.13 I disagree, because both of these example describe work done with complete
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`promoters (pTEF and pAOX1, respectively). These Examples do not describe any “promoter
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`elements” within these promoters, nor do these portions of the specification use the term
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`“promoter element” at all.
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`18. Moreover, these examples do not provide any guidance as to what aspects of these
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`complete promoters “drive transcription of genes.”14 Dr. Alper recognizes that promoters may
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`have sequences that are “dispensable for driving transcription.”15 These examples (and the
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`specification more generally) shed no light on which sequences of the complete promoter are
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`“dispensable” and which are not, let alone guidance on how the POSA should go about making
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`this determination.
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`3.
`
`The art cited by Dr. Alper does not show that the POSA would be able
`to determine the scope of “promoter element” with any reasonable
`certainty
`
`19.
`
`Dr. Alper cites to various references that use the term “promoter element” to
`
`
`
`13 Alper III ¶ 33.
`14 Alper III ¶ 33.
`15 Alper III ¶ 28.
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`6
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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 9 of 24 PageID #: 22807
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`support his opinion that the POSA would know what a “promoter element” is.16 While these
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`references do use the phrase “promoter element,” they use it in different ways. And none of
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`them would allow a POSA to determine the scope of “promoter element” in the claims of the
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`Yeast Patents with any reasonable certainty, for the reasons summarized below.17
`
`20.
`
`Redden & Alper (Alper Exhibit 2): Redden & Alper is a paper published July
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`17, 2015. Redden & Alper use the term “promoter element” (without further modifier) twice:
`
`Promoters serve a critical role in establishing baseline
`transcriptional capacity for nearly every natural and synthetic
`circuit or pathway1,2. These elements can synthetically impart
`controlled, tuneable, inducible, responsive and/or coordinated
`function of a circuit3–5. Such precise control is critical for varied
`applications from balancing components within a responsive
`circuit to preventing build-up of toxic intermediate metabolites
`along a pathway6. Thus, promoter elements are indispensable
`synthetic biology parts and, not surprisingly, are among the first to
`be annotated and developed for new hosts.
`
`…
`
`As such, two of the most commonly used yeast promoter elements,
`the GAL1 inducible promoter and the strong GPD (TDH3)
`promoter span over 400 and 600 nucleotides respectively.
`
`From context, it would be clear to the POSA that Redden & Alper are using the term “promoter
`element” in these passages interchangeably with the term “promoter.” Redden & Alper also
`refer on several occasions to “core promoter elements.” For example:
`
`Isolation of robust and minimal core promoter elements. These 18
`putative core elements were next assessed through a series of
`robustness tests (Fig. 1b).
`
`
`
`16 Alper III ¶ 27.
`17 Several of the pieces of art cited by Dr. Alper post-date May 2015, and thus I understand that
`they would not be considered as reflecting the understanding of the POSA as of May 2015. I
`have been asked to consider this art anyway. Whether this art is considered or not, it does not
`change my overall opinion.
`
`
`7
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`

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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 10 of 24 PageID #: 22808
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`…
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`A generic workflow for isolating minimal, core promoter elements
`was followed.
`
`…
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`By linking minimal UAS elements with a core promoter element,
`synthetic promoters approaching GPD strength can be assembled.
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`The reported research is directed to isolating “minimal core elements” (also referred to as
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`“minimal core promoter elements”) and combining them with “UAS elements,” which are also
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`involved in the regulation of transcription, but are not referred to as any type of “promoter
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`elements.”18 Dr. Alper cites the references to “minimal core elements” as showing the POSA
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`would know the scope of what a “promoter element” is,19 but this reference does not use
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`“promoter element” in isolation, as discussed above.
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`21.
`
`Li (Alper Exhibit 3): Li is a paper published April 25, 2007. Li states:
`
`Most P. pastoris expression systems use the methanol-induced
`alcohol oxidase (AOX1) promoter [1]. Upon induction by
`methanol, the fraction of total soluble protein that is composed of
`alcohol oxidase can typically rise to 30% [2], indicating the power
`of this promoter element.
`
`There is no other reference to “promoter element” in this paper. From context, the POSA would
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`understand Li to be referring to the complete AOX1 promoter when it refers to “this promoter
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`element,” and understand that Li does not distinguish between a promoter and promoter
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`elements.
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`22.
`
`Suppmann (Alper Exhibit 4): Suppmann is a patent which I understand has a
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`priority date of no later than December 2004. It explicitly defines the term “promoter element”:
`
`A “promoter” is a regulatory nucleotide sequence that stimulates
`transcription. These terms are understood by those of skill in the
`
`
`18 Redden & Alper at 2.
`19 Alper III ¶ 28.
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`8
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`art of genetic engineering. Like a promoter, a “promoter element”
`stimulates transcription but constitutes a sub-fragment of a
`larger promoter sequence.
`
`Suppmann at 2:3-67. The POSA reading this would understand that a “promoter element” is not
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`a complete promoter, according to Suppmann, but is part of a promoter sequence that still
`
`stimulates transcription.
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`23.
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`Zhang (Alper Exhibit 5): Zhang is a patent which I understand has a priority
`
`date of no later than March 2012. Zhang also explicitly defines the term “promoter element”:
`
`Promoter or Promoter element: As used herein, the terms
`“promoter” and “promoter element” refer to a polynucleotide that
`regulates expression of a selected polynucleotide sequence
`operably linked to the promoter, and that effects expression of the
`selected polynucleotide sequence in cells.
`
`Zhang at 10:44-48. From this passage, the POSA would recognize that Zhang uses the terms
`
`“promoter” and “promoter element” to refer to the same thing.
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`24.
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`U.S. Patent No. 11,702,665 (Alper Ex. 6): U.S. Patent No. 11,702,665 is a
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`patent, which I understand has a priority date of no later than November 15, 2018. This patent
`
`uses the term “promoter element” twice. It is not used in the claims. The two references to
`
`“promoter element” are:
`
`In some aspects, the nucleic acid molecule is operatively linked to
`a promoter element that is heterologous to at least one of the
`second polynucleotide sequence and Paenibacillus.
`
`…
`
`In one aspect, the nucleic acid molecule is operatively linked to a
`promoter element that is heterologous to at least one of the second
`polynucleotide sequences and Paenibacillus.
`
`U.S. Patent No. 11,702,665 at 5:12-15 & 9:5-8. The specification refers to “promoters”
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`9
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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 12 of 24 PageID #: 22810
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`repeatedly, however.20 In my opinion, the POSA would therefore reasonably assume that
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`“promoter element,” in this patent, means the same thing as “promoter.” The term “promoter
`
`element” is not used in the claims of this patent.
`
`25. WO 2015/148680: WO 2015/148680 is a patent application, which I understand
`
`has a priority date of no later than March 25, 2014. This application explicitly defines “promoter
`
`element” alongside “promoter”:
`
`As used herein, the terms "promoter," "promoter element," or
`"promoter sequence" refer to a DNA sequence which when ligated
`to a nucleotide sequence of interest is capable of controlling the
`transcription of the nucleotide sequence of interest into mRNA.
`
`WO 2015/148680 at [0060]. After this passage, it provides further general description of several
`
`promoter elements:
`
`One should appreciate that promoters have modular architecture
`and that the modular architecture may be altered. Bacterial
`promoters typically include a core promoter element and additional
`promoter elements. The core promoter refers to the minimal
`portion of the promoter required to initiate transcription. A core
`promoter includes a Transcription Start Site, a binding site for
`RNA polymerases and general transcription factor binding sites.
`The "transcription start site" refers to the first nucleotide to be
`transcribed and is designated +1. Nucleotides downstream of the
`start site are numbered +1, +2, etc., and nucleotides upstream of
`the start site are numbered -1, -2, etc. Additional promoter
`elements are located 5' (i.e., typically 30-250 bp upstream of the
`start site) of the core promoter and regulate the frequency of the
`transcription. The proximal promoter elements and the distal
`promoter elements constitute specific transcription factor site.
`
`WO 2015/148680 at [0061]. In the first passage no distinction is made between promoter,
`
`promoter element or promoter sequence that would inform a POSA of the difference between the
`
`three terms. In the second passage a “core promoter element” is mentioned as being contained
`
`within a promoter but then the term “core promoter” is used. A POSA would not be clear
`
`
`20 For example, see 12:46-49, 29:12-14, 30:12-15, 32:3-6, 32:6-15.
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`10
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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 13 of 24 PageID #: 22811
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`whether a “core promoter” is distinct or different from a “core promoter element,” nor would it
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`be reasonably certain to a POSA what non-core promoter elements may exist beyond the
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`“proximal” and “distal” promoter elements generally referenced in this passage. Perhaps for this
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`reason, the term, “promoter element” does not appear in the claims.
`
`26.
`
`U.S. Patent Appl. No. 2023/0257793: U.S. Patent Application No. 2023/0257793
`
`is a patent application, which I understand has a priority date of no earlier than September 5,
`
`2020. Dr. Alper refers to this patent application and its discussion of a “core promoter
`
`element.”21 That discussion is as follows:
`
`Aspects of the disclosure relate to a methylotrophic host cell
`comprising a synthetic expression system that comprises the
`following elements: (1) a first transcriptional unit comprising an
`input promoter comprising an upstream activating sequence (UAS)
`and a core promoter element . . . .
`
`U.S. Patent Application No. 2023/0257793 at [0006].22 This paragraph uses the term “core
`
`promoter element,” not “promoter element” more generally, and would therefore be of limited
`
`use to the POSA trying to determine the scope of the term “promoter element” in the claims of
`
`the Yeast Patents.
`
`27.
`
`I note that in U.S. Patent Application No. 2023/0257793 the “core promoter
`
`element” is described as part of a promoter involved in regulation of transcription, for example at
`
`paragraph [0006] (“an input promoter comprising an upstream activating sequence (UAS) and a
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`core promoter element”) and [0357] (“As used in this application, a ‘core promoter’ refers to the
`
`minimal portion of a promoter that is required to initiate transcription and that includes the
`
`transcriptional start site.”). The application also discusses sequences for this “core promoter
`
`element” in detail, for example at paragraphs [0026]-[0027]. The application also refers to
`
`21 Alper III ¶ 32.
`22 Cited by Dr. Alper in paragraph 32.
`
`
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`11
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`“upstream activating sequence” or “UAS.” Upstream activating sequences are sequences that, in
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`general, regulate a promoter, and therefore also regulate transcription. U.S. Patent Application
`
`No. 2023/0257793 describes UAS as part of the promoter, for example at [0006]. However, the
`
`unmodified term “promoter element” is not used to describe the UAS.
`
`28.
`
`In addition to these references, other references also reflect varied use of the term
`
`“promoter element.” For example, Hartner (previously discussed by me and also referenced in
`
`the declaration of Dr. Lin-Cereghino) describes two nucleotides as an “element” within the
`
`AOX1 promoter.23 In my previous declaration of June 28, 2023, I also discussed Vogl &
`
`Glieder. Vogl & Glieder describe various “elements” that they isolated from promoters
`
`experimentally. The definition of an “element” in that paper was a consequence of the way they
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`isolated them through that process. In contrast, Hartner used a computational approach, which
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`resulted in different “elements” (including from the same promoters) being identified.24 This is
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`because, as I explained in my June 28, 2023 declaration, the relationship between promoter
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`structure (e.g., sequence and location thereof) and promoter function (e.g., effect on gene
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`expression) is determined empirically. So, if a different empirical method is used, it could result
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`in different subsequences being identified as “elements” of the same promoter.
`
`29.
`
`To be clear, I do not dispute that the literature uses the term “promoter element”
`
`and that a POSA would have some general sense of its intended meaning. But this does not
`
`mean that the scope of the term “promoter element” in the Yeast Patents would be reasonably
`
`certain to the POSA. It would not be. The references discussed above confirm that the term
`
`“promoter element” is used outside the context of the Yeast Patents in various ways: complete
`
`23 Lin-Cereghino ¶ 66.
`24 Additional detail is provided in my June 28, 2023 declaration at paragraphs 161-165.
`
`
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`12
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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 15 of 24 PageID #: 22813
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`promoter (Li, Redden & Alper, Zhang, U.S. Patent No. 11,702,655), subsets of nucleotides
`
`within a promoter that appear to have some effect on transcription (Hartner), subsets of
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`nucleotides within a promoter that stimulate transcription (Suppmann), certain pieces of a
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`promoter with specific functions and locations (WO 2015/148680), or regions of a promoter as
`
`defined by the specific research methodology used by the scientist (Hartner, Vogl & Glieder).
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`Collectively, rather than supporting Dr. Alper’s opinions, these references confirm there is no
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`common, accepted and reasonably certain scope to the term “promoter element,” even today.
`
`30.
`
`As is apparent, the literature uses the term “promoter element” in different ways.
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`The specification of the Yeast Patents does not provide any guidance as to what meaning or
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`scope that term should have among the various uses of the term in the literature.
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`31.
`
`The Redden & Alper reference, on which Dr. Alper is a co-author, also supports
`
`my opinion for an additional reason. In that paper, Dr. Alper and his co-author reported their
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`work to isolate and identify “minimal core elements.” Dr. Alper uses the term “minimal core
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`elements” to refer to the smallest sequences that he experimentally determined were “(1) []
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`generically activated by any UAS or TFBS, (2) function with alternative genes and (3) display
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`little context dependence.”25 This is yet another competing definition of what a promoter
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`element might be. In order to identify these “minimal core elements,” Dr. Alper started with a
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`“pool of 15 million [core element] candidates.”26 From that pool of 15 million candidates, nine
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`“minimal core elements” were identified.27 They were described as “highly unique both among
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`each other and to any native genomic sequences in S. cerevisiae” (S. cerevisiae was the yeast
`
`
`
`25 Redden & Alper at 3.
`26 Id. at 2.
`27 Id.
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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 16 of 24 PageID #: 22814
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`they studied).28 Dr. Alper identified these nine “minimal core elements” only through what they
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`described as “a series of rigorous tests[.]”29
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`32.
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`The fact that Dr. Alper and his co-author published these results in July 2015
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`confirms that the full scope of sequences that correspond to the claimed “promoter element”
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`would not have been reasonably certain to the POSA in 2015. While the paper refers to (albeit
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`undisclosed) “essential sequences for promoter function” (Ex. 6 at 2), Dr. Alper’s work confirms
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`that the minimal sequences sufficient for promoter functionality had to be determined through
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`extensive experimentation.
`
`33.
`
`Dr. Alper’s paper also demonstrates that it is not clear where one should draw the
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`line for what a “promoter element” is or is not. The only reference to “promoter element” in the
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`paper without additional modifier suggests a “promoter element” is the complete promoter. In
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`his declaration, Dr. Alper cites Redden & Alper for suggesting some sequence less than the
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`complete promoter constitutes a “promoter element.”30 But how is that sequence characterized?
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`For example, are the 15 million candidate sequences Dr. Alper tested “promoter elements”? Are
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`the “promoter elements” only the nine sequences that met the three requirements that they were
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`generically activated by any UAS/TFBS, functioned with alternative genes, and were context
`
`independent (i.e. the “minimal core promoter elements”)? Or is the “promoter element” defined
`
`by sequences within the pools of nine sequences and 15 million sequences? For example, are
`
`there sequences that met only one or two of Dr. Alper’s three requirements (such as sequences
`
`that are context dependent for their function) for a “minimal core element” that still qualify as
`
`“promoter elements”? As Dr. Alper’s paper shows, what a “promoter element” is depends on
`
`
`
`28 Id.
`29 Id.
`30 Alper III ¶ 28.
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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 17 of 24 PageID #: 22815
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`where the POSA draws the line on what function is sufficient, what should be tested to determine
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`that function, and how that test should be carried out.
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`B.
`
`34.
`
`Term 2a - “a Mxr1 transcriptional activator sequence” (’492 Patent, claim 1)
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`Term 2a and the constructions I understand have been proposed by Ginkgo,
`
`Motif, and Impossible are below.
`
`Term
`No.
`
`2a
`
`
`
`Claim Term
`
`Ginkgo’s Proposed
`Construction
`
`Motif’s Proposed
`construction
`
`a sequence of an Mxr1
`transcriptional
`activator protein /
`a sequence of an Mxr1
`transcriptional
`activator protein found
`naturally in P. pastoris
`
`the sequence of the
`native P. pastoris
`Mxr1 transcriptional
`activator
`
`
`“a Mxr1
`transcriptional
`activator
`sequence” /
`“a Mxr1
`transcriptional
`activator sequence
`from P. pastoris”
`
`(’492 Patent: all
`asserted claims)
`
`Impossible’s
`Proposed
`Construction
`the sequence to
`which the Mxr1
`transcriptional
`activator binds31
`
`35.
`
`Dr. Alper does not dispute that the specification discusses sequences encoding the
`
`Mxr1 protein, as discussed in my January 12, 2024 declaration at paragraphs 91-98.32 He also
`
`does not dispute that the specification contains virtually no discussion of binding of
`
`transcriptional activator proteins generally, and does not discuss or disclose sequences to which
`
`the Mxr1 protein binds, as discussed in my January 12, 2024 declaration at paragraphs 99-100.33
`
`36.
`
`Despite this lack of support in the specification, Dr. Alper maintains that Term 2a
`
`
`31 Previously, I understand Impossible had stated that its construction was “the consensus
`sequence that actually binds the [Mxr1] protein.” I understand that Impossible has since updated
`its proposed construction.
`32 Alper III ¶ 40. In this paragraph, he does not dispute my analysis or identification of this
`discussion in the specification.
`33 Alper III ¶ 41. In this paragraph, he does not dispute my analysis or suggest the specification
`contains additional discussion of sequences to which the Mxr1 transcriptional activator binds.
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`Case 1:22-cv-00311-WCB Document 347 Filed 02/02/24 Page 18 of 24 PageID #: 22816
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`refers to the sequence to which Mxr1 protein binds, not the sequence encoding the Mxr1
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`transcriptional activator protein. He opines that defining “Mxr1 transcriptional activator
`
`sequence” to mean the sequence encoding the Mxr1 transcriptional activator “does not make
`
`sense in the context of