# Presentation: 049354

## Obviousness in view of KSR

**TC1600-Specific Examples**

## The Basic Approach to Determining Obviousness Remains the Same

***KSR International Co. v. Teleflex Inc., *** **550 U.S. —, ****82 USPQ2d 1385 (2007)**
**An examiner is **_**still**_** required to provide a reasoned statement of rejection grounded in the *****Graham***** inquiries.  He or she must articulate a reason or rationale to support the obviousness rejection.  **
**See *****KSR***** at 1396  ("To facilitate review, [the obviousness] analysis should be made explicit.") (citing *****In re Kahn*****, 441 F.3d 977, 988 (Fed. Cir. 2006)).**

**Notes:**
The basic approach to determining  obviousness remains the same.
KSR provides an expansive view of prior art. 
KSR emphasizes that any reasoned argument grounded in the Graham inquiries may form the basis for a holding of obviousness. 

## Any Reasoned Argument Grounded in Graham May Form the Basis for a Prima Facie Case of Obviousness

**"If a court, or patent examiner, conducts [the *****Graham*****] analysis and concludes the claimed subject matter was obvious, the claim is invalid under § 103.” *****KSR***** at 1391.  **
**"The obviousness analysis cannot be confined by a formalistic conception of the words teaching, suggestion, and motivation, or by overemphasis on the importance of published articles and the explicit content of issued patents." *****KSR***** at 1396. **

## The Examiner as Fact Finder

**Examiners act as fact finders when resolving the *****Graham***** inquiries. **
**Examiners must articulate findings  of fact to support the obviousness rejection being made.****  **

**Notes:**
The finder of fact determines what one of ordinary skill would have known at the time of the invention, and what such a person would have reasonably expected to have been able to do in view of that knowledge.  

This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. 

When making an obviousness rejection, examiners are only required to make an explicit statement addressing the level of ordinary skill in the art when the level of ordinary skill is not clear in light of the cited prior art.  

Most of the time, the prior art itself reflects an appropriate level of skill. 

The factfinder should be aware, of course, of the distortion caused by hindsight bias and must be cautious of arguments reliant upon hindsight reasoning.") (citing Graham, 383 U.S. at 36).

## Key Points

**Examiners **_**must**_** account for all claim limitations in their rejections  by explaining how each limitation is disclosed or rendered obvious by the reference(s) applied**

## Key Points

**Prior art is not limited to the four corners of the documentary prior art being applied.**
**Prior art includes both the specialized understanding of one of ordinary skill in the art, and the common understanding of the layman. **
**It includes "background knowledge possessed by a person having ordinary skill in the art. . . .  [A] court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ."  *****KSR***** at 1396.  **

## Making a Prima Facie Case of Obviousness

**Examiners must: **
**Resolve the *****Graham *****inquiries**
**Articulate appropriate factual findings**
**Explain the reasoning that provides a nexus between the factual findings and the legal conclusion of obviousness**

## Rationales

**One or more of the rationales set forth in the following slides may be relied upon to support a conclusion of obviousness **
**The list of rationales provided herein is not intended to be an all-inclusive list**
**The key to supporting any rejection under 35 U.S.C. § 103 is the **_**clear articulation**_** of the reasons why the claimed invention would have been obvious.**

**Notes:**
Note that the rationales that follow are culled from the KSR decision, but are not exclusive. The distinctions between them may appear slight.  Often, more than one rationale may be applicable to a given set of facts and evidence. 
MPEP § 2144 discusses various rationales which may be used to support a conclusion of obviousness.  

## Rationales Supporting a Prima Facie Case of Obviousness

- Combining prior art elements according to known methods to yield predictable results
- Simple substitution of one known, equivalent element for another to obtain predictable results
- Use of known technique to improve similar devices (methods, or products) in the same way
- Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results

**Notes:**
As I go through the examples that follow, be aware that these are being used for illustration only.  
None of these examples is determinative of a conclusion for any other fact pattern.  
All determinations of obviousness are to be made based on the facts of each individual case.

I have tried, wherever possible, to provide examples in pairs, for contrast and comparison.

I will provide the claims, the prior art, any other evidence, followed by the conclusion.

## Rationales Supporting a Prima Facie Case of Obviousness

- "Obvious to try" – choosing from a finite number of predictable solutions
- Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations would have been predictable to one of ordinary skill in the art
- Teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings

**Notes:**
As I go through the examples that follow, be aware that these are being used for illustration only.  
None of these examples is determinative of a conclusion for any other fact pattern.  
All determinations of obviousness are to be made based on the facts of each individual case.

I have tried, wherever possible, to provide examples in pairs, for contrast and comparison.

I will provide the claims, the prior art, any other evidence, followed by the conclusion.

## Example 1

**Claims**
**A therapeutic composition comprising hematopoietic stem cells obtained from umbilical cord blood and a cryopreservative**
**A method for hematopoietic or immune reconstitution comprising cryopreservation of hematopoietic stem cells obtained from umbilical cord blood , thawing, and administering said cells to a human**

## Example 1

**Prior Art**
**Reference identifies the presence of stem cells in umbilical cord blood**
** **
**Reference teaches that stem cells in umbilical cord blood could be cryopreserved and thawed **
**Reference suggests the use of stem cells from cord blood for transplantation and hematopoietic reconstitution**

## Example 1

**Evidence **
**Declarations by expert asserting**
**Prior art used “flawed nomenclature”**
**Problems with prior transplants of analogous stem cells (blood, marrow)**
**Surprise by those in the art at the success of the invention**

**Notes:**
Expert testified that what the prior art calls “stem cells” were really progenitors.

Evidence presented of problems with previous transplants with stem cells from marrow and blood.

Evidence presented that those in the field were surprised at the success of the first transplant.

## Example 1

**Evidence**
**Statements in the specification defining both stem cells **_**and**_** progenitors are consistent with art-recognized definitions of stem cells and progenitors**

**Notes:**
In the specification, the inventors stated “Human hematopoietic stem cells have been demonstrated in human umbilical cord blood, by colony formation, to occur at a much higher level than that found in the adult.”  The fact that they were talking specifically about stem cells the court found was implied by Applicants’ own statement immediately following that quote that stated “the presence of hematopoietic progenitor cells in human fetal blood has also been shown.”

What would you conclude?

## Example 1

**Conclusion**
**It would have been obvious to one of ordinary skill in the art at the time the invention was made to collect, cryopreserve, store and administer hematopoietic stem cells from umbilical cord blood to an individual in need of hematopoietic reconstitution with a reasonable expectation of success because the prior art suggests that umbilical cord blood may be successfully used in hematopoietic reconstitution and may be successfully cryopreserved without loss of viability of the stem cells contained therein**

**Notes:**
This analysis uses the TSM rationale.

## Pharmastem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 83 USPQ2d 1289 (Fed. Cir. 2007)

**Court’s Analysis**
**Could not reconcile expert testimony with statements in the specification**
**Did not agree with expert that terminology was “flawed”**
**Prior art references to “stem cells” were consistent with Applicants’ statements in the specification**
**Citing KSR, determined that invention was confirmation of what was already believed to be true**

**Notes:**
Strongly worded dissent by Judge Newman
Majority 
Engaged in impermissible hindsight
Ignored peer response
Ignored jury verdict
Ignored scientific experts
Ignored agency expertise

## Example 2

**Claim**
**The besylate salt of amlodipine**

## Example 2

**Prior Art**
**Patent disclosing amlodipine and pharmaceutically-acceptable acid addition salts and specifically names hydrochloride, hydrobromide, sulphate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, and gluconate salts**
**Reference disclosing 53 FDA-approved commercially-marketed anions useful for making pharmaceutically acceptable salts and specifically names besylate as one of those salts whose frequency of use was 0.25%**

## Example 2

**Evidence**
**Inventor declaration asserting that the besylate salt of amlodipine possessed good solubility, stability, non-hygroscopicity and processability which were “unpredictable both individually and collectively” and was superior to prior art amlodipine maleate salt**

**Notes:**
What would you conclude?

## Example 2

**Conclusion**
**It would have been obvious to one of ordinary skill in the art at the time the invention was made to choose from a finite number of predictable pharmaceutically acceptable salt  options of amlodipine with a reasonable expectation of success of producing a functional amlodipine formulation**

## Pfizer, Inc. v. Apotex, Inc.,  480 F.3d 1348, 82 USPQ2d 1321 (Fed. Cir. 2007)

**Court’s Analysis**
**Suggestion, teaching or motivation does not have be explicit and “may be found in any number of sources, including common knowledge, the prior art as a whole or the nature of the problem itself”, citing Dystar Textilfarben GMBH v. C.H. Patrick Co., 464 F.3d 1356 (Fed. Cir. 2006) **
**Formulations must be tested by routine procedures to verify expected properties**

**Notes:**
This is a case that was decided after oral arguments for KSR but before the ruling by the Supreme Court in KSR. 

The Federal Circuit could see the writing on the wall! 

## Example 3

**Claim**
**5-4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl-2,4-thiazolidinedione (a thiazolidinedione (TZD) with the ethyl group at the 5-position pyridyl ring) **

**Notes:**
TZDs are used to treat diabetes. The first TZD to be marketed in the United States was troglitazone, known by the commercial name Rezulin(R), in 1997. 
Two years after Rezulin(R) entered on the market, the FDA approved GlaxoSmithKline's Avandia(R) (whose active ingredient is rosiglitazone). 
This compound is known as pioglitazone

## Example 3

**Prior Art **
**Patent disclosing ****an effective anti-diabetic compound,**** “Compound 42” (out of 60), which differs from ****the claimed compound in two ways**
**methyl in place of ethyl**
**substitution in the 6-position instead of the 5-position**
**References discussing the conventional practices of homologation and ring-walking**
**	****	**

**Notes:**
Compound #42 was the closest structurally to the claimed compound.

## Example 3

**Prior Art **
**Review article of 101 TZD compounds, which specifically singles out “Compound 42” as having negative side effects of increasing body weight and percentage brown fat **
**	****	**

**Notes:**
The reference points out 3 most promising TZDs, none of which were “compound 42”.
It further singles out “compound b” as having negative side effects. 
Increased body weight and percentage brown fat are to be avoided in individuals with type 2 diabetes; obesity exacerbates type 2 diabetes and can actually cause diabetes.  

## Example 3

**Evidence**
**Compound 42 produced significant toxicity to the liver and heart as well as a decrease in the  number of erythrocytes, a sign of potential toxicity to bone marrow**
**Claimed compound showed no statistically significant toxicity**
**	****	**

**Notes:**
What would you conclude?

## Example 3

**Conclusion**
**The claimed compound would **_**not**_** have been obvious to one of ordinary skill in the art at the time the invention was made due to evidence of teaching away and unexpected properties**
**	****	**

**Notes:**
If the evidence had not been present on the record at the time of first office action, it may have been appropriate to reject the claims using the rationale of obvious to try a finite number of predictable solutions using homologation and ring walking; however, once the evidence had been presented, the rejection would have to have been dropped.

## Takeda Chemical Industries v. Alphapharm Pty, Ltd., 492 F.3d 1350, 83 USPQ2d 1169 (Fed. Cir. 2007)

**Court’s Analysis**
**No “finite number of identifiable, predictable solutions” **
**Prior art provided “broad selection of compounds”**
**Closest prior art compound exhibited negative properties**** **

## Highlights and Guidance

**Evidence is critical to the determination of obviousness**
**Example 1 - Applicants’ statements in specification were consistent with the prior art and inconsistent with expert testimony**
**Example 2 – Evidence of unexpected results may be insufficient to overcome a conclusion of obviousness**
**Example 3 - Evidence of “teaching away” combined with unexpected results were sufficient to outweigh evidence of obviousness**

**Notes:**
In Pharmastem, Applicants’ statements in the specification appeared consistent with statements in the prior art such that the expert testimony was given less weight.

In Pfizer, the evidence of routine pharmacological testing procedures outweighed the assertion that the besylate salt had superior properties

In Takeda, teaching away and unexpected results combined with large number of compounds disclosed was outside of the “finite number of predictable solutions”.

Remember to weigh the evidence:  There is no magic key or combination – there are no per se rules – it is a case-by-case analysis.

Unexpected results may or may not be sufficient to outweigh evidence of obviousness.
Similarly, a teaching away may or may not be sufficient to outweigh the evidence of obviousness.
Remember also to consider the scope of the claims in comparison to any evidence of nonobviousness.

## Example 4

**Claim**
**Solid oral dosage form comprising**
**(a) coated famotidine granules**
**(b)  Al(OH)****3**** or Mg(OH)****2**** granules**
**wherein the coating on the famotidine is impermeable to the Al(OH)****3**** or Mg(OH)****2**** **

**Notes:**
Famotidine is PepcidAC and Famotidine formulated with antacids is Pepcid Complete.  
Famotidine is incredibly bitter.  
Applicants found that the coating of the famotidine decreases the bitterness 

## Example 4

**Prior Art**
**Reference disclosed combination of uncoated histamine H****2**** receptor antagonists (e.g. famotidine) and antacids**
**Reference disclosed coating granulated medicaments to mask taste of active ingredient**
**Reference acknowledged the bitter taste of cimetidine (a famotidine analog)**

**Notes:**
Reference teaches that the combination of histamine h2 receptor antagonists and antacids increase bioavailability of antagonist.
Famotidine is specifically listed as antagonist, and Al(OH)3 or Mg(OH)2 are specifically listed as antacids.
The reference does not disclose any taste issues of the antagonists but does permit the inclusion of palatability aids.

## Example 4

**Evidence**
**Other modes of taste-masking were preferable due to cost of coated granules**

**Notes:**
What would you conclude?

## Example 4

**Conclusion**
**It would have been obvious to one of ordinary skill in the art at the time the invention was made to apply a known taste-masking technique to mask the expected bitter taste of famotidine by coating the famotidine granules with the predictable expectation that the formulation will be more palatable**

**Notes:**
The rationale was Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results.

## McNeil-PPC, Inc. v Perrigo Company, 516 F. Supp.2d 238 (S.D. N.Y. July 3, 2007)

**Court’s Rationale**
**The combination of coated famotidine and the antacids provided no more than predictable results, citing KSR**
**Costs alone are not indicative of non-obviousness**

## Example 5

**Claim**
**A formulation comprising**
**(a) a core comprising omeprazole plus an alkaline reacting compound (ARC);**
** ****(b) an inert subcoating, which is soluble or rapidly disintegrates in water, disposed on the core region, **
**(c) an outer layer disposed on the subcoating comprising an enteric coating**** **

**Notes:**
Omeprazole is Prilosec, a treatment for GERD

## Example 5

**Prior Art**
**References disclose drugs formulated in a core with a subcoating and enteric coating but do not disclose omeprazole**
**References disclose omeprazole but do not disclose coatings or an alkaline reacting compound **
**References describe subcoating techniques but do not disclose omeprazole – subcoatings should not be used with moisture-sensitive drugs**

**Notes:**
Drugs + subcoating and coating but no disclosure of omeprazole

Omeprazole but no disclosure of coatings or alkaline reacting compound

Subcoatings should not be used with moisture sensitive drugs.

## Example 5

**Evidence**
**Omeprazole is acid labile, sensitive to heat, moisture, solvents and light**
**Expert testimony of “multitude of possible paths and dead-ends” in formulation attempts**

**Notes:**
What would you conclude?

## Example 5

**Conclusion**
**It would **_**not**_** have been obvious to one of ordinary skill in the art at the time the invention was made to formulate omeprazole with an alkaline reacting compound and then sub-coat and enterically coat the combination**

## In re Omeprazole Patent Litigation, 490 F. Supp. 2d 381 (S.D. N.Y. June 1, 2007)

**Court’s Analysis**
**Prior art compounds that were subcoated and coated were not comparable to omeprazole**
**Prior art taught away from the subcoated formulation**
**Prior art disclosure to omeprazole formulations did not disclose stability problems**

**Notes:**
Teaching away from using subcoating with moisture-sensitive drugs; omeprazole is moisture-sensitive.

Subcoated and coated prior art compounds needed to be delivered in part to the stomach; omeprazole needs to be delivered to the upper intestine in its entirety.

Patentees discovered that omeprazole actually interacted with the enteric coating, which was the need for the subcoating – to protect the omeprazole from the necessary enteric coating.

Distinguishes facts in KSR as a predictable upgrade, versus genuine innovation in this case.

## Highlights and Guidance

**Recognition of problems in the prior art as well as answers to problems in the prior art may lead to a finding of obviousness**
**In Example 4, single problem is solved with predictable results**
**In Example 5, numerous variables suggested that the results would not be predictable**

## Example 6

**Claim**
**An isolated nucleic acid molecule comprising a polynucleotide encoding a polypeptide at least 80% identical to amino acids 22 – 221 of SEQ ID NO:2, wherein the polypeptide binds CD48**

**Notes:**
NK Cell Activation Inducing Ligand (NAIL) polypeptides are cell surface marker/receptor on NK cells that modulates the activity of NK cells.  
CD48 is a membrane glycoprotein on hematopoeitic cells.  
Discovery that NAIL binds CD48 allows the production of molecules that modulate the activation of NK cells.   

## Example 6

**Prior Art**
**Reference disclosed p38 protein (same protein as NAIL) and methods of isolation by using mAbs as well as methods of obtaining the polynucleotide sequence but does not disclose the sequence of p38**
**Reference disclosed the nucleic acid sequence of the highly conserved murine version of p38 and identified a human homologue**

**Notes:**
What would you conclude?

## Example 6

**Conclusion**
**One of ordinary skill in the art would have been motivated to isolate and identify the claimed nucleotide sequence based on the prior art disclosure of the p38 protein by applying conventional methodologies**

**Notes:**
"Obvious to try" – choosing from a finite number of predictable methodologies

## Ex parte Kubin, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007)

**Board’s Analysis**
**State of the art has advanced**
**Reliance on KSR – “obvious to try” in view of limited methodologies available to isolate NAIL cDNA**
**Methodologies had reasonable expectation of success**

**Notes:**
Some may view this decision as inconsistent with the holding in In re Deuel.  However, this decision does not overturn Deuel.  This case is on appeal to the Federal Circuit and will be decided in 2008.  We will have to wait to see what the Federal Circuit does.  
If you have a similar fact pattern and you are trying to decide which side of the fence to come down on, consult with others and come by and we’ll talk and get consensus for your particular facts.

## Highlights and Guidance

**Advancements in the state of the art may render that which was once unpredictable to become predictable**
**Regularly review the state of the art that is examined**
**Take of note of changes in the state of the art**

**Notes:**
That which was unpredictable can become predictable overnight.  Relying on outdated information can lead to incorrect conclusions during examination.   

## Example 7

**Claim**
**An antivenom pharmaceutical composition for treating a snakebite victim, comprising**
**Fab fragments which bind specifically to a venom of a snake of the Crotalus genus essentially free from contaminating Fc**
**and a pharmaceutically acceptable carrier, **
**which neutralizes the lethality of the venom of a snake of the Crotalus genus**

**Notes:**
Rattlesnakes are found within the genus Crotalus.

## Example 7

**Prior Art**
**Reference teaches whole antibodies purified from horse serum for use as an antivenom for treatment of rattlesnake bites**
**Reference teaches producing Fab fragments from whole antibodies for use in immunoassays to detect textilotoxin**

**Notes:**
Textilotoxin is the venom of the Australian brown snake

## Example 7

**Evidence**
**Declaration discussing state of the art of antivenoms which, since 1969, have only been commercially available as whole antibodies or F(ab)2 fragments**
**Declaration stating that those in the art would not have considered Fab fragments as antivenoms because they are cleared faster than whole antibodies or F(ab)2 fragments**

## Example 7

**Evidence**
**Declaration discussing success of whole antibody antivenom dependent on extra disulfide bond allowing whole antibody to bind to repeating protein antigens - Fab fragment does not contain such a bond but surprisingly binds and neutralizes venom**
**Declaration showing decreased adverse immune reactions**

**Notes:**
Whole antibodies have shown adverse immune reactions

## Example 7

**Conclusion**
**To be determined!**
**Federal Circuit vacates decision of the Board that affirmed the Examiner’s conclusion of obviousness**
**Remanded to the Board for evaluation of rebuttal evidence**

## In re Sullivan, 498 F.3d 1345, 84 USPQ2d 1034 (Fed. Cir. 2007)

**Court’s Analysis**
**The Board asserted that the declarations related only to use and expressly declined to give any meaningful consideration to them because the claims were drawn to the composition**
**The court found that the board erred in failing to consider rebuttal evidence**

**Notes:**
Court states that the Board’s focus on the intended use “misses the mark”.    The Board cited In re Zierden, 411 F.2d 1325 (CCPA 1969) as standing for the proposition that a statement of a new use for an otherwise old or obvious composition cannot render a claim to the composition patentable.  In Zierden, applicant admitted that the composition claimed was distinguished from the prior art only by the recitation of intended use.  In this case, Applicants did not concede that their composition was old and since the rejection was not made under 102, it is apparent that the examiner agreed.  In this case, the application extensively argued that the claimed composition exhibited unexpected properties of neutralizing the lethality of rattlesnake venom with reducing the occurrence of adverse immune reactions in humans, thereby asserting a lack of obviousness of the composition itself.  

## Highlights and Guidance

**Do not ignore any terms in a claim**
**Determine whether any claimed function requires or implies a structural limitation**
**Explain how the prior art renders obvious the functional limitation, i.e. how the invention rendered obvious by the prior art is suitable for and/or capable of carrying out the claimed function**

## Example 8

**Claim**
**A method for treating otopathy which comprises the topical otic administration of an amount of ofloxacin or a salt thereof effective to treat otopathy in a pharmaceutically acceptable carrier to the area affected with otopathy**

## Example 8

**Prior Art**
**Reference teaches lack of ototoxicity of ciprofloxacin when used to treat middle ear infections**
**Reference teaches that ofloxacin and ciprofloxacin are both gyrase inhibitors and belong to the same family of compounds**

## Example 8

**Conclusion**
**It would have been obvious to one of ordinary skill in the art at the time the invention was made to substitute ofloxacin for ciprofloxacin in the treatment of otopathy with a predictable expectation of successful treatment due to the compounds’ structural and functional similarities**

**Notes:**
Simple substitution of one known, equivalent element for another to obtain predictable results

## Daiichi Sankyo Co. v. Apotex, Inc.,501 F.3d 1254, 84 USPQ2d 1285 (Fed. Cir. 2007)

**Court’s Analysis**
**District Court erred in the determination of the level of skill**
**By finding the level of skill in the prior art to be too high, prior art teaching was dismissed by the District Court**

**Notes:**
While the facts of the case seem very simple and straightforward, the case was before the Federal Circuit because the disagreement as to the level of ordinary skill in the art of the claimed invention.

District Court found that reference was aimed at an otologist (an ear specialist), which was a person of extraordinary skill in the art.  Since the otologist was outside the level of ordinary skill in the art (a general practitioner), the prior art teaching would not have rendered the claimed invention obvious to one of ordinary skill in the art.

## Highlights and Guidance

**Resolving the level of ordinary skill may be explicit or implicit in view of the prior art applied**
**When making an obviousness rejection, examiners are only *****required***** to make an explicit statement addressing the level of ordinary skill in the art when the level of ordinary skill is not clear in light of the cited prior art (Union Carbide Corp. v. American Can Co., 724 F.2d 1567, 1573 (Fed. Cir. 1984))**

**Notes:**
Union Carbide:  "We hold only that an invention may be held to have been either obvious (or nonobvious) without a specific finding of a particular level of skill or the reception of expert testimony on the level of skill where, as here, the prior art itself reflects an appropriate level.

In most cases, the prior art itself implicitly resolves the level of ordinary skill.  Rarely will it be necessary to explicitly resolve the level of ordinary skill in an obviousness rejection.

## Example 9

**Claim**
**The 5(S) stereoisomer of ramipril substantially free of other isomers**

**Notes:**
Ramipril has 5 stereocenters.  The claimed isomer has all stereocenters in the S configuration.

## Example 9

**Prior Art**
**References teach that related ACE-inhibiting therapeutic compounds (BPP5a, captopril, and enalapril) are most therapeutically active in the S configuration**
**“****Parent” patent disclosing structurally similar compounds and teaching that when diastereomeric products result from the synthetic procedures, the diasteriomeric products can be separated by conventional chromatographic or fractional crystallization methods**

**Notes:**
ACE inhibitors are inhibitors of Angiotensin Converting Enzymes in the Renin-Angiotensin System. 
The system in general aims to increase blood pressure 
BPP5a, a compound isolated from Brazilian viper venom, has six stereocenters, all in the S configuration.
Enalapril has three stereocenters and the 3S stereoisomer has 700 times the potency of the SSR stereoisomer.  The all S isomer was isolated using standard chromatographic techniques.
Captopril has two stereocenters, both of which remain in the S configuration.

Lack of continuity between parent and child resulted in parent patent being prior art against child application.  

## Example 9

**Evidence**
**Synthesis of a mixture of the 5(S) stereoisomer with the 4(S)(R) stereoisomer of ramipril by competitor pharmaceutical company (which qualified as prior art under 102(g))**

## Example 9

**Conclusion**
**It would have been obvious to one of ordinary skill in the art at the time the invention was made to produce and isolate the 5(S) stereoisomer of ramipril with a reasonable expectation of success**

**Notes:**
Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results

## Aventis v. Lupin,499 F.3d 1293, 84 USPQ2d 1197(Fed. Cir. 2007)

**Court’s Analysis**
**District Court erred in requiring clear and convincing showing of motivation, citing KSR**
**Obviousness flowed from recognition of the properties of similar prior art compounds combined with recognition of the presence of the claimed isomer in the prior art mixture**

**Notes:**
Structural similarity created an expectation of similar properties and there was a reasonable expectation that the separation techniques would work

## Example 10

**Claim**
**Substantially pure (S) enantiomer of escitalopram oxalate**

**Notes:**
Escitalopram is an antidepressant which works as a selective serotonin re-uptake inhibitor.  There is only 1 chiral center in escitalopram.

## Example 10

**Prior Art**
**Reference taught racemate of escitalopram as a SSRI and predicted enhanced potency of the (R) enantiomer but did not disclose the process of separation of the racemate**

**Notes:**
SSRI – selective serotonin re-uptake inhibitor – class of antidepressants

## Example 10

**Evidence**
**Chiral HPLC was a relatively new and unpredictable technique at the time of the invention**
**Author of prior art reference had attempted to use chiral HPLC to separate racemate of escitalopram but failed**
**Failure by inventor to resolve escitalopram racemate by diasteriomeric salt formation**

**Notes:**
Remember - this was at the time of the invention.  

## Example 10

**Conclusion**
**It would **_**not**_** have been obvious to one of ordinary skill in the art at the time the invention was made to produce the substantially pure (S) enantiomer of escitalopram oxalate with a reasonable expectation of success**

## Forest Laboratories v Ivax Pharmaceuticals,501 F.3d 1263, 84 USPQ2d 1099(Fed. Cir. 2007)

**Court’s Analysis**
**District Court’s finding that the prior art reference was not enabling with regard to the isolation of (S) enantiomer was not in error**

## Highlights and Guidance

**Evidence**
**Consider the invention as a whole and all of the evidence presented**
**The question under 35 U.S.C. 103 is not whether the differences themselves would have been obvious, but whether the claimed invention as a whole would have been obvious**

**Notes:**
Certainly, the basic facts of the Forest v. Ivax case appear on their face simpler, with only one chiral center, versus five chiral centers in the Aventis case.  However, the outcomes were based on the evidence when considering the invention as a whole.   To say that separating isomers from racemates is obvious ignores the compounds in question as well as any evidence, i.e. the invention as a whole. Distilling an invention down to the “gist” or “thrust” of an invention disregards the requirement of analyzing the subject matter “as a whole.”

## Example 11

**Claim**
**A transgenic corn plant that produces a Bt protein where the foreign DNA nucleic acid coding sequence has a G+C content of at least about 60%**

**Notes:**
Fertile transgenic corn plants that express a gene encoding a Bt insecticidal protein so as to cause mortality to European corn borers ("ECB"). 
Bt is a soil bacteria that produces proteins toxic to certain insect pests, but is not harmful to humans. 
For many years, farmers sprayed formulations of Bt bacteria onto crops as pesticides. 
With the advances in the field of plant biotechnology came expression of genes encoding the production of the Bt insecticidal protein in plants. 

## Example 11

**Prior Art**
**Published patent application describing a method for improving Bt expression in tobacco plant genes by selecting codons that are rich in G+C to increase expression efficiency of the Bt protein and asserting that the methodology would be equally applicable in other plant species**

**Notes:**
Native microbial Bt genes have a high proportion of codons rich in A+T while plants generally display an opposite bias towards codons that are rich in G+C.  
By looking at the preferred codon table in the application and selecting the codon occurring at the highest frequency for each amino acid, one would obtain a Bt gene with a G+C content of over 60%

## Example 11

**Evidence**
**Declaration showing total sales of transgenic corn and asserting commercial success**

## Example 11

**Conclusion**
**It would have been obvious to one of ordinary skill in the art to modifying the Bt DNA sequence by selecting codons for the Bt amino acid sequence that are rich in G+C with a reasonable expectation of improved expression of Bt in by the corn plant and optimizing the percentage G+C to produce desired expression**

**Notes:**
This is a TSM analysis.

## Syngenta Seeds v. Monsanto,(Fed. Cir. 2007)

**Court’s Analysis**
**A non-precedential decision after KSR **
**District Court correctly used the Graham factors**

**Notes:**
District Court decision in 2005 – explicitly states “In determining obviousness, the court uses the four-part test set forth in Graham v. John Deere Co., 383 U.S. 1, 86 S. Ct. 684, 15 L. Ed. 2d 545 (1966). Iron Grip Barbell Co. Inc. v. USA Sports, Inc., 392 F.3d 1317, 1320 (Fed. Cir. 2005). 

## Highlights and Guidance

**When deciding questions of obviousness**
**Determine the facts**
**Weigh the evidence – including secondary considerations**
**Articulate rationales**
**Explain conclusions**

**Notes:**
When determining the facts, consider all claim limitations.  Patentability is found in the differences between the claims and the prior art.  Focusing on the similarities and ignoring the differences can lead to erroneous conclusions.

When weighing evidence, consider the scope of the claims compared to the scope of the evidence. 

Finally, evidence of an unexpected property may not be sufficient regardless of the scope of the showing, if the facts supporting the conclusion of obviousness are very strong.

When articulating rationales, be clear and as specific as possible.

When explaining conclusions, point to the facts that support the conclusions.  Explain how the facts give the context under which one of ordinary skill in the art would view the facts so that the conclusion of obviousness is the only option.  

## Thank You!

**Jean Witz, tQAS TC1600**
**2-0927**
**Remsen 4D25**